Reactions of amines and hydrazides derived from L-proline with dialkyl dicyanofumarates

Article abstract of DOI:10.3987/COM-12-S(N)16

The reaction of prolinamine derivatives (8a,b) and dialkyl dicyanofumarates (1) in dichloromethane at room temperature leads to the optically active enamines (10). Whereas products (10) in the case of 1-benzyl prolinamine (8a) are stable compounds, the corresponding enamines obtained from the non-protected prolinamine (8b) smoothly undergo a cyclocondensation at room temperature to give perhydropyrrolo[1,2-a]pyrazine derivatives (11). The molecular structure of 11a was established by X-Ray crystallography. In analogy to 8a, 1-benzyl prolinehydrazide (9a) and 1b in dichloromethane react to yield the enehydrazine (12b). On the other hand, the reaction of 9a and 1 in methanol at room temperature leads to the corresponding dialkyl 3-amino-1H-pyrazole- 4,5-dicarboxylates (13) and methyl 1-benzylprolinate (14b) Via a stepwise mechanism. The analogous reaction was observed between a 3-oxidoimidazole-4- carbohydrazide (15) and 1b.

Full text of DOI:10.3987/COM-12-S(N)16

HETEROCYCLES, Vol. 86, No. 1, 2012
343
HETEROCYCLES, Vol. 86, No. 1, 2012, pp. 343 - 356. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 14th May, 2012, Accepted, 15th June, 2012, Published online, 18th June, 2012
DOI: 10.3987/COM-12-S(N)16
REACTIONS OF AMINES AND HYDRAZIDES DERIVED FROM
L-PROLINE WITH DIALKYL DICYANOFUMARATES
Grzegorz Mlosto!,a* Adam M. Pieczonka,1,a Aneta Wróblewska,2,a Anthony
Linden,b and Heinz Heimgartnerb*
a: University of !ód", Department of Organic and Applied Chemistry, Tamka 12,
PL-91-403 !ód", Poland: e-mail: gmloston@uni.lodz.pl
b: University of Zurich, Institute of Organic Chemistry, Winterthurerstrasse 190,
CH-8057 Zurich, Switzerland; e-mail: heimgart@oci.uzh.ch
Dedicated to Professor Dr. Ei-ichi Negishi on the occasion of his 77th birthday
Abstract – The reaction of prolinamine derivatives (8a,b) and dialkyl
dicyanofumarates (1) in dichloromethane at room temperature leads to the
optically active enamines (10). Whereas products (10) in the case of 1-benzyl
prolinamine (8a) are stable compounds, the corresponding enamines obtained
from the non-protected prolinamine (8b) smoothly undergo a cyclocondensation
at room temperature to give perhydropyrrolo[1,2-a]pyrazine derivatives (11). The
molecular structure of 11a was established by X-Ray crystallography. In analogy
to 8a, 1-benzyl prolinehydrazide (9a) and 1b in dichloromethane react to yield the
enehydrazine (12b). On the other hand, the reaction of 9a and 1 in methanol at
room temperature leads to the corresponding dialkyl 3-amino-1H-pyrazole-
4,5-dicarboxylates (13) and methyl 1-benzylprolinate (14b) via a stepwise
mechanism. The analogous reaction was observed between a 3-oxidoimidazole-4-
carbohydrazide (15) and 1b.
INTRODUCTION
In a series of our recent papers, reactions of electron-deficient dicyanofumarates (1) with N- and
O-nucleophiles were reported.3–6 For example, in the case of !-amino alcohols (2), the reaction occurs
stepwise and, after initial formation of the #-hydroxyalkylenamine (3), subsequent cyclocondensation
affords morpholinone derivatives (4)6 (Scheme 1).

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HETEROCYCLES, Vol. 86, No. 1, 2012
NC
CO2R
CO2R
CN
R4
R1
H
N
R2
R1
HO
R3
R4
NH2
NC
CO2R
CN
R3
R2
CH2Cl2, rt
-HCN
3
RO C
2
NH
R
R4
-ROH
RO2C
R2
R1
O
O
HO
1
2
3
4
Scheme 1
Similarly, reactions of diethyl dicyanofumarate (1a) with 1,2-diamines open a convenient access to
2-oxopiperazine derivatives.7 Unexpectedly, hydrazine hydrate reacts with 1a (R = Et) and 1b (R = Me)
to give the pyrazol-3(2H)-one derivatives (6)6 (Scheme 2).
NC
RO2C
O
.
NC
CO2R
R = Me, Et
-ROH
NH2NH2 H2O
NH
RO2C HN NH2
EtOH, rt
-HCN
N
H
5
6
NC
CO2R
CN
RO2C
RO2C
H2N
CO2R
1a-c
R'NHNH2
a: R = Et
b: R = Me
c: R = iPr
N
N
EtOH, reflux
AcONa
R'
7
R' = Ar, H2NCO
Scheme 2
The intermediate (5) was isolated as a stable compound in the case of the sterically congested isopropyl
ester (1c, R = iPr) and did not cyclize even after prolonged heating. In contrast to hydrazine,
arylhydrazines as well as semicarbazide react with 1 in boiling ethanol in the presence of sodium acetate
yielding 5-aminopyrazole derivatives (7) as the final products.8
In two recent publications, reactions of 1a with aromatic carbohydrazides were described, and in both
cases two types of products were isolated.9 One of them was identified as a 1-substituted pyrazol-5-one
derivative of type 6, and the second one was described as a 1,3,4-oxadiazin-6-one derivative in the first
paper but then as a 1,3,4-oxadiazole derivative in the second one.
Due to our ongoing interest in the preparation of enantiomerically pure bis-heterocycles derived from
L-proline,10 we became interested in reactions of dicyanofumarates (1) with [(2S)-pyrrolidin-2-yl]-

HETEROCYCLES, Vol. 86, No. 1, 2012
345
methylamines (8a,b, ‘prolinamines’) and proline hydrazides (9a, b), respectively.
RESULTS AND DISCUSSION
The reaction of N-benzyl prolinamine (8a) with dimethyl dicyanofumarate (1b) in dichloromethane
occurred smoothly at room temperature, and the expected enamine (10b) was isolated after
chromatography in good yield (79%) as a pale yellow oil (Scheme 3). Its structure was confirmed by
spectroscopic data which fitted well with those of earlier reported ‘push-pull’ enamines of this type.4 The
1
13
proposed (Z)-configuration of 10b is supported by H- and C-NMR data. Firstly, the NH-absorption at
9.80 ppm indicates an intramolecular hydrogen bond with the ester group. Secondly, three characteristic
signals for sp2-C atoms, attributed to two C=O groups and to C(3) of the but-2-enedioate, appear at 168.2,
161.9, and 161.3 ppm. The signal of C(2) was characteristically shifted to high field and was found at
70.8 ppm. The analogous products 10a and 10c were obtained in good yields starting with diethyl and
diisopropyl dicyanofumarate, respectively.
R = Bn
10a R = Et (57%)
10b R = Me (79%)
10c R = iPr (81%)
N
CO2R
CN
HN
Bn
CH2Cl2
rt, 15 min
RO2C
NH2
1a-c
N
R
8a R = Bn
8b R = H
N
11a R = Et (79%)
11b R = Me (64%)
11c R = iPr (74%)
R = H
NH
CO2R
CH2Cl2
O
rt, 15 min
NC
Scheme 3
The corresponding experiment with non-protected prolinamine (8b) and 1b was also carried out at room
temperature, and the 1H-NMR spectrum of the crude reaction mixture, registered after 10 min, evidenced
the presence of 11b as the sole product. The analogous reaction was observed with 8b and 1a, and even in
the case of the bulky diisopropyl dicyanofumarate (1c), no intermediate enamine of type 10 could be
detected after 10 min at room temperature. Fractional crystallization of the crude mixtures gave
analytically pure products, which were identified as the bicyclic 2-oxopiperazine derivatives (11)
(Scheme 3). The structure of 11a was unambiguously confirmed by X-Ray crystallography (Figure 1).

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HETEROCYCLES, Vol. 86, No. 1, 2012
Figure 1. ORTEP plot11 of the molecular structure of one of the symmetry-independent molecules in the
crystal structure of 11a (arbitrary numbering of the atoms; 50% probability ellipsoids)
Figure 2. Packing diagram of 11a showing the hydrogen bonding interactions (uninvolved hydrogen
atoms omitted for clarity)
There are two of the enantiomerically pure molecules in the asymmetric unit whose conformations differ
by slightly different puckering of the six-membered ring and a significantly different orientation of the
terminal ester methyl group (ca. 165° rotation about the ester O–C bond). The amine group forms
bifurcated hydrogen bonds. One is an intramolecular interaction with the ester carbonyl O atom
[N(1)–H···O(11) and N(21)–H···O(31)] which can be described by a graph set12 motif of S(10). The other

HETEROCYCLES, Vol. 86, No. 1, 2012
347
is an intermolecular interaction with the cyano group [N(1)–H···N(2’) and N(21)–H···N(22’)] which links
the independent molecules into separate extended chains which run parallel to the [100] direction (Figure
2). This interaction can be described by a graph set motif of C(6).
The mechanistic pathway leading to the bicyclic products (11) leads via the initially formed enamine type
(10), which results from the preferred nucleophilic addition of the primary amino group.4,6 In the second
step, a cyclocondesation occurs with the secondary amino group. The latter reaction takes place in a
selective manner with the ester group leading to the six-membered lactam.7
Along with prolinamines (8), the N-benzyl protected L-proline hydrazide (9a) was reacted with
dicyanofumarates (1). The first experiment was performed in dichloromethane at room temperature with
9a and 1b. After 10 min, the solvent was evaporated and a colorless solid was obtained. On the basis of
the spectroscopic data, the structure of this product was elucidated as the enehydrazine derivative (12b)
(Scheme 4). For example, the IR spectrum (KBr) shows strong absorptions of a C!N and three C=O
groups at 2202, 1752, 1667, and ca. 1660 cm-1. In addition, a very intense absorption at 1559 cm-1 is
1
attributed to the C=C bond of the ‘push-pull’ enehydrazine structure.4 The H-NMR spectrum indicates
the presence of two MeO groups, with absorptions at 3.95 and 3.81 ppm, and the N-benzylpyrrolidine
moiety.
MeO2C
H
N
CN
NC
CO2Me
CN
H
CH2Cl2
NH2
N
N
H
N
R
N
rt, 10 min
-HCN
CO2Me
MeO2C
O
O
Bn
1b
9a (R = Bn)
12b (56%)
Scheme 4
In order to examine cyclization reaction of compound 12b, a sample of 12b was dissolved in commercial
1
CDCl3 (for the NMR usage) and was periodically controlled by H-NMR spectroscopy. Unexpectedly,
after 24 h, the starting compound (12b) was converted into new products, which subsequently were
separated by preparative TLC. The more polar fraction was obtained as colorless crystals, which showed
1
only three signals in the H-NMR spectrum at 3.83 and 3.94 ppm (2 MeO), and 6.10 ppm. The latter
disappeared after addition of D2O. In the IR spectrum (KBr), a prominent absorption at 3281 cm–1
indicated the presence of amino groups. The HR-ESI-MS (MeCN + NaI) showed the [M+Na]+ peak at
13
m/z 222.04834 corresponding with the molecular formula C7H9N3O4. In addition, the C-NMR spectrum
revealed the presence of two methyl ester groups (51.1/52.6 and 152.9/163.9 ppm) and only three
additional signals at 93.5, 142.5, and 164.6 ppm. Based on these data, the structure of the isolated product
was formulated as dimethyl 5-aminopyrazole-3,4-dicarboxylate (13b), i.e. the N-unsubstituted analogue

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HETEROCYCLES, Vol. 86, No. 1, 2012
of the earlier reported products of the reactions of arylhydrazines with dicyanofumarates8 (Scheme 5).
The less polar fraction was also isolated and identified as ethyl N-benzylprolinate (14a).13
MeO2C
H
MeO2C
H2N
CO2Me
CN
CDCl3
N
+
N
H
N
CO2Et
EtOH
(trace)
rt
N
H
N
N
CO2Me
O
Bn
Bn
12b
13b
14a
RO2C
H2N
CO2R
MeOH, rt
+
9a 1a-c
+
N
CO2Me
N
N
H
Bn
13a R = Et (80%)
13b R = Me (44%)
13c R = iPr (56%)
14b
Scheme 5
The formation of products 13b and 14a results from the ethanolysis of 12b by traces of ethanol in the
used CDCl3. Prompted by this observation, a sample of 12b was dissolved in methanol and, after 1 h at
1
room temperature, the H-NMR spectrum confirmed the presence of 13b and methyl N-benzylprolinate
(14b). Moreover, when equimolar amounts of diethyl dicyanofumarate (1a) and hydrazide (9a) were
dissolved in methanol at room temperature, already after 5 min a colorless solid was formed. After 30
min, again a clear solution was observed, and after evaporation of the solvent and chromatographic
workup, the two products (13a) and (14b) were obtained in ca. 1:1 ratio. The same protocol was used in
reactions of 9a with 1b and 1c leading to the expected 13b and 13c, respectively, in addition to 14b.
Two other experiments were performed in order to evaluate the reactivity of proline hydrazides (9)
towards dicyanofumarates (1). In one case, proline hydrazide (9b, R = H) was reacted with an equimolar
1
amount of 1b in methanolic solution. After 1 h, the reaction was complete, and the H-NMR analysis of
the reaction mixture again confirmed the presence of 13b side by side with methyl prolinate. This result
points out that the NH2 group of the hydrazide reacts faster with 1b than the proline NH group.
In analogy to our previous study,5 a three-component reaction of equimolar amounts of
F
9a, 1b, and 3-(4-fluorophenyl)-2,2-dimethyl-1-azabicyclo[1.1.0]butane (15) was
1
carried out in methanol at room temperature. The H-NMR analysis of the reaction
mixture performed after 1 h confirmed the presence of unconverted azabicyclobutane
along with 13b and 14b. Thus, the nucleophilicity of the hydrazide exceeds that of the
1-azabicylo[1.1.0]butane derivative.
15
Me
Me
N

HETEROCYCLES, Vol. 86, No. 1, 2012
349
In an extension of the study with proline hydrazides (9), the hydrazide (16), derived from imidazole
N-oxide, was reacted with 1b in ethanol. After 16 h at room temperature, two major products were
formed and by comparison with original samples identified as 13b and ethyl
2-oxoimidazole-4-carboxylate (17) (Scheme 6).14 The latter is formed via the known thermal
isomerization of the corresponding 3-oxidoimidazole-4-carboxylate formed in situ via ethanolysis of the
initially formed enehydrazine like 12.
O
NH2
NH
CO2Et
Me
MeO2C
H2N
CO2Me
O
NC
CO2Me
CN
HN
EtOH
N
N
O
N
rt, 16 h
Me
MeO2C
N
H
N
Bn
Bn
16
1b
13b
17
Scheme 6
It is worth mentioning that in all experiments carried out with hydrazides (9a) and (16), no formation of
pyrazolones, 1,3,4-oxadiazinones, or 1,3,4-oxadiazoles, suggested as isolated products in earlier reports,9
was observed. Therefore, the reactions of 1b with 9a and 16 were performed also in boiling ethyl acetate.
In both cases, after heating for 4 h, complex mixtures of non-identified products were obtained, and the
attempted chromatographic separation was unsuccessful.
CONCLUSIONS
The present study shows that prolinamines (8a,b) smoothly react with the electron-deficient
dicyanofumarates (1a-c) leading, in the initial step, after elimination of HCN, to enamines of type 10. In
the case of the non-protected prolinamine (8b), subsequent cyclocondensation leads smoothly to
enantiomerically pure bicyclic oxopiperazine derivatives (11) in a selective manner. Compounds of that
type are of potential interest as building blocks for the preparation of biologically active, bicyclic
heterocycles.15 Proline derived hydrazides undergo the reaction with 1 via addition of the NH2 group onto
the C,C-double bond. The enhydrazines (12) obtained thereafter, display remarkable reactivity toward
alcohols and are easily cleaved to the corresponding ester and the non-substituted enehydrazines. The
latter undergo selective cyclization with the C!N group forming 3-aminopyrazoles (13). The formation of
these products deserves a brief comment. As described in our previous paper,5 the enehydrazines obtained
from dicyanofumarates and hydrazine hydrate, which are believed to posses the (Z)-configuration,
undergo selectively the alternative cyclocondensation, i.e. lactamization. A plausible explanation for the
observed discrepancy in the cyclization step, e.g. the presence of differently configured enehydrazines, is
not available yet.

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HETEROCYCLES, Vol. 86, No. 1, 2012
EXPERIMENTAL
General remarks. Melting points were determined in a capillary using a Melt-Temp. II (Aldrich) or
STUART SMP30 apparatus and they are uncorrected. The IR Spectra were recorded on a NEXUS FT-IR
spectrophotometer in KBr; absorptions (!) in cm–1. The 1H- and 13C[1H]-NMR spectra were measured on
a Bruker Avance III (600 and 150 MHz, resp.) instrument using solvent signals as reference. Chemical
13
shifts (!) are given in ppm and coupling constants J in Hz. Assignments of signals in C-NMR spectra
were made on the basis of HMQC experiments. HR-ESI-MS: Bruker maXis spectrometer. Optical
rotations were determined on a PERKIN-ELMER 241 MC polarimeter for " = 589 nm.
Starting materials. All solvents are commercially available and used as received. Dimethyl-, diethyl-,
and diisopropyl dicyanofumarates (1a–1c) were prepared from the corresponding cyanoacetates by
treatment with thionyl chloride according to the published general procedure.16 [(2S)-Pyrrolidin-2-yl]-
methylamines (8a,b),17a,b proline hydrazides (9a,b),10,18 and 3-oxidoimidazole-4-carbohydrazide (16)19
were prepared according to known procedures.
General procedure for the preparation of compounds 10 and 11. To a magnetically stirred solution of
the corresponding dialkyl dicyanofumarate (1, 1 mmol) in CH2Cl2 (2 mL) at rt, a solution of 8a or 8b (1
mmol) in CH2Cl2 (2 mL) was added dropwise. When the addition was complete, stirring was continued
for 15 min, and then the solvent was evaporated to dryness. The crude product was purified by PLC
(SiO2).
Diethyl (2Z)-2-({[(2S)-1-benzylpyrrolidin-2-yl]methyl}amino)-3-cyanobut-2-enedioate (10a). Yield:
20
220 mg (57%). Pale yellow oil. [!]D –135 (c 0.4, CH2Cl2). IR (film): v 3226m, 2978m, 2211s (CN),
1746s (C=O), 1674s, 1588s, 1274m, 1044m, 785m. 1H-NMR (CDCl3): " 9.81 (s, 1H, NH); 7.38–7.22 (m,
5 arom. H); 4.42 (q, JH,H = 7.2 Hz, 2H, MeCH2); 4.31–4.23 (m, 2H, MeCH2); 3.87 (d, JH,H = 13.2 Hz, 1H,
PhCH2); 3.47 (d, JH,H = 13.2 Hz, 1H, PhCH2); 3.31–3.25 (m, 1H, HC(6’)); 3.18–3.12 (m, 1H, HC(6’));
3.09–3.04 (m, 1H, HC(5’)); 2.84–2.78 (m, 1H, HC(2’)); 2.32–2.26 (m, 1H, HC(5’)); 2.01–1.93 (m, 1H,
HC(3’)); 1.76–1.69 (m, 2H, H2C(4’)); 1.68–1.61 (m, 1H, HC(3’)); 1.40 (t, JH,H = 7.2 Hz, 3H, MeCH2);
13
1.33 (t, JH,H = 7.2 Hz, 3H, MeCH2). C-NMR (CDCl3): " 167.91 (C(2)=C); 161.57, 161.41 (2 C=O);
139.22 (arom. C); 128.81, 128.56, 127.35 (5 arom. CH); 117.15 (CN); 70.93 (C=C(3)); 63.70 (MeCH2);
62.05 (C(2’)); 61.10 (MeCH2); 58.89 (PhCH2); 54.76 (C(5’)); 48.21 (C(6’)); 28.66 (C(3’)); 23.44 (C(4’));
14.03, 14.55 (2 MeCH2). ESI-HRMS (MeOH+0.1% HCOOH): 386.20757(calcd.386.20743 for
C21H27N3O4, [M+1]+)
Dimethyl (2Z)-2-({[(2S)-1-benzylpyrrolidin-2-yl]methyl}amino)-3-cyanobut-2-enedioate (10b).

HETEROCYCLES, Vol. 86, No. 1, 2012
351
Yield: 283 mg (79%). Pale yellow oil. [!]D20 –133 (c 1.0 CH2Cl2). IR (film): v 3228m, 2954m, 2211s (CN),
1748s (C=O), 1680s, 1589s, 1281m, 1045m, 796m. 1H-NMR (CDCl3): " 9.80 (s, 1H, NH); 7.38–7.23 (m,
5 arom. H); 3.94 (s, 3H, MeO); 3.86 (d, JH,H = 13.21 Hz, 1H, PhCH2); 3.81 (s, 3H, MeO); 3.48 (d, JH,H
=
13.21 Hz, 1H, PhCH2); 3.30–3.26 (m, 1H, HC(6’)); 3.16–3.11 (m, 1H, HC(6’)); 3.09–3.05 (m, 1H,
HC(5’)); 2.84–2.79 (m, 1H, HC(2’)); 2.32–2.27 (m, 1H, HC(5’)); 2.01–1.93 (m, 1H, HC(3’)); 1.75–1.69
13
(m, 2H, H2C(4’)); 1.66–1.59 (m, 1H, HC(3’)). C-NMR (CDCl3): " 168.19 (C(2)=C); 161.93, 161.30 (2
C=O); 139.16 (arom. C); 128.81, 128.59, 127.37 (5 arom. CH); 117.17 (CN); 70.81 (C=C(3)); 61.99
(C(2’)); 58.88 (PhCH2); 54.78 (C(5’)); 53.87, 52.11 (2 Me); 48.32 (C(6’)); 28.65 (C(3’)); 23.47 (C(2’)).
ESI-HRMS (MeOH+0.1% HCOOH): 358.17619 (calcd. 358.17613 for C19H23N3O4, [M+1]+).
Diisopropyl (2Z)-2-({[(2S)-1-benzylpyrrolidin-2-yl]methyl}amino)-3-cyanobut-2-enedioate (10c).
Yield: 333 mg (81%). Pale yellow oil. [!]D20 –135 (c 0.4 CH2Cl2). IR (film): v 3223m, 2980m, 2211s (CN),
1743s (C=O), 1668s, 1588s, 1277m, 1100m, 700m. 1H-NMR (CDCl3): " 9.80 (s, 1H, NH); 7.38–7.35 (m,
2 arom. H); 7.32–7.28 (m, 2 arom. H); 7.25–7.22 (m, 1 arom. H); 5.29–5.23 (m, 1H, Me2CH); 5.13–5.08
(m, 1H, Me2CH); 3.88 (d, JH,H = 13.21 Hz, 1H, PhCH2); 3.36 (d, JH,H = 13.21 Hz, 1H, PhCH2); 3.30–3.25
(m, 1H, HC(6’)); 3.18–3.12 (m, 1H, HC(6’)); 3.08–3.03 (m, 1H, HC(5’)); 2.83–2.78 (m, 1H, HC(2’));
2.31–2.26 (m, 1H, HC(5’)); 2.00–1.92 (m, 1H, HC(3’)); 1.76–1.69 (m, 2H, HC(4’)); 1.68–1.62 (m, 1H,
HC(3’)); 1.39, 1.38 (2d, JH,H = 6.24 Hz, 6H, 2 Me2CH); 1.31, 1.30 (2d, JH,H = 6.60, 6.54 Hz, 6H, 2
13
Me2CH). C-NMR (CDCl3): " 167.55 (C(2)=C); 161.52, 161.18 (2 C=O); 139.27 (arom. C); 128.82,
128.55, 127.33 (5 arom. CH); 117.13 (CN); 72.29 (Me2CH); 71.05 (C=C(3)); 68.68 (Me2CH); 62.10
(C(2’)); 58.90 (PhCH2); 54.76 (C(5’)); 48.07 (C(6’)); 28.65 (C(3’)); 23.43 (C(4’)); 22.09, 22.08, 21.71,
21.68 (2 Me2CH). ESI-HRMS (MeOH+0.1% HCOOH): 414.23874 (calcd. 414.23873 for C23H32N3O4,
[M+1]+).
Ethyl
(2Z)-2-[(8aS)-4-oxo-1,2,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-3-ylidene]-2-cyanoacetate
20
(11a). Yield: 198 mg (79%). Pale yellow crystals, mp 213–214 °C (CH2Cl2/hexane). [!]D +534 (c 1.0
1
CH2Cl2). IR (KBr): v 3443m, 3208m, 2204s (CN), 1664s (C=O), 1585s, 1243s, 1174s, 796m. H-NMR
(CDCl3): " 10.06 (s, 1H, NH); 4.29–4.22 (m, 2H, MeCH2); 3.91–3.85 (m, 1H, HC(8a’)); 3.75–3.62 (m,
3H, HC(6’), H2C(1’)); 3.24–3.19 (m, 1H, HC(6’)); 2.28–2.22 (m, 1H, HC(8’)); 2.14–2.09 (m, 1H,
HC(7’)); 1.96–1.88 (m, 1H, HC(7’)); 1.69–1.61 (m, 1H, HC(8’)); 1.33 (t, JH,H = 7.20 Hz, MeCH2).
13C-NMR (CDCl3): " 169.4, 156.7 (2 C=O); 155.2 (C(3’)=C); 116.7 (CN); 73.9 (C=C(2)); 61.5 (MeCH2);
55.9 (C(8a’)); 45.9 (C(1’)); 45.7 (C(6’)); 30.7 (C(8’)); 23.1 (C(7’)); 14.4 (MeCH2). ESI-HRMS
(MeOH+NaI): 272.10049 (calcd. 272.10056 for C12H15N3NaO3, [M+Na]+).
Methyl (2Z)-2-[(8aS)-4-oxo-1,2,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-3-ylidene]-2-cyanoacetate

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HETEROCYCLES, Vol. 86, No. 1, 2012
(11b). Yield: 152 mg (64%). Pale yellow crystals, mp 240–242 °C (decomp., CH2Cl2/hexane). [!]D20 +294
(c 1.0 CH2Cl2). IR (KBr): v 3439m, 3211m, 2210s (CN), 1663s (C=O), 1592s, 1252s, 1194s, 797m.
1H-NMR (CDCl3): " 10.03 (s, 1H, NH); 3.92–3.85 (m, 1H, HC(8a’)); 3.81 (s, 3H, MeO); 3.75–3.62 (m,
3H, HC(6’), H2C(1’)); 3.25–3.19 (m, 1H, HC(6’)); 2.29–2.23 (m, 1H, HC(8’)); 2.15–2.08 (m, 1H,
13
HC(7’)); 1.96–1.87 (m, 1H, HC(7’)); 1.69–1.61 (m, 1H, HC(8’)). C-NMR (CDCl3): " 169.5, 156.7 (2
C=O); 155.3 (C(3’)=C); 116.7 (CN); 73.3 (C=C(2)); 55.9 (C(8a’)); 52.4 (MeO); 46.0 (C(1’)); 45.7
(C(6’)); 30.7 (C(8’)); 23.1 (C(7’)). ESI-HRMS (MeOH+NaI): 258.08485 (calcd. 258.08491 for
C11H13N3NaO3, [M+Na]+).
Isopropyl (2Z)-2-[(8aS)-4-oxo-1,2,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-3-ylidene]-2-cyano-
20
acetate (11c). Yield: 196 mg (74%). Pale yellow crystals, mp 200–202 °C (CH2Cl2/hexane). [!]D +507
(c 1.0 CH2Cl2). IR (KBr): v 3442m, 2983m, 2209s (CN), 1675s (C=O), 1601s, 1253s, 1110s, 770m.
1H-NMR (CDCl3): " 10.08 (s, 1H, NH); 5.09–5.01 (m, 1H, Me2CH); 3.93–3.84 (m, 1H, HC(8a’));
3.75–3.61 (m, 3H, HC(6’), H2C(1’)); 3.24–3.18 (m, 1H, HC(6’)); 2.27–2.21 (m, 1H, HC(8’)); 2.13–2.02
(m, 1H, HC(7’)); 1.95–1.86 (m, 1H, HC(7’)); 1.68–1.60 (m, 1H, HC(8’)); 1.31, 1.30 (2d, JH,H = 6.00 Hz,
Me2CH). 13C-NMR (CDCl3): " 168.9, 156.6 (2 C=O); 155.5 (C(3’)=C); 116.7 (CN); 74.2 (C=C(2)); 69.3
(Me2CH); 55.9 (C(8a’)); 45.9 (C(1’)); 45.7 (C(6’)); 30.6 (C(8’)); 23 (C(7’)); 22.0, 21.9 (Me2CH).
ESI-HRMS (MeOH+NaI): 286.11607 (calcd. 286.11621 for C13H17N3NaO3, [M+Na]+).
Preparation of dimethyl 2-{[N2-(1-benzylpyrrolidin-2-yl)carbonyl]hydrazino}-3-cyanobut-2-ene-
dioate (12b). To a solution of hydrazide (9a, 1 mmol) in 1 mL of CH2Cl2, 1 mmol of dicyanofumarate
(1b) was added in portions. The mixture was stirred for 10 min at rt, and the solvent was removed under
vacuum to give 12b as yellowish solid. Yield: 200 mg (56%). Yellowish solid, mp 162–165 °C (EtOH).
[!]D20 –103 (c 1.0, CH2Cl2). IR (KBr): 3220m (NH), 2955w, 2202s (C!N), 1752vs (C=O), 1667vs (C=O),
1559s, 1281s. 1H-NMR (CDCl3): 7.33–7.18 (m, 5 arom. H); 7.10 (br.s, NH); 4.42–4.40 (m, CH); 3.95 (s,
MeO); 3.87 (d, J = 12.6 Hz, 1H, PhCH2); 3.81 (s, MeO); 3.64 (d, J = 12.6 Hz, 1H, PhCH2); 3.16–3.14 (m,
1H), 2.52–2.38 (m, 2H); 1.95–1.82 (m, 3H). 13C-NMR (CDCl3): 176.6, 92.3 (C=C); 163.1, 162.8, 153.9 (3
C=O); 146.3 (1 arom. C); 129.0, 128.1, 127.2 (5 arom. CH); 114.9 (C!N); 64.4 (CH); 58.7 (PhCH2); 52.7,
51.3 (2 MeO); 54.6, 30.1, 23.3 (3 proline CH2). HR-ESI-MS (MeCN+HCOOH): 387.16658 (calcd.
387.16630 for C19H23N4O5, [M+H]+).
Reactions of hydrazides (9a, b) and (16) with dicyanofumarates (1). – General procedure. To a
solution of hydrazide 9 or 16 (1 mmol) in 1 mL of MeOH (or EtOH), 1 mmol of 1 was added and the
mixture was stirred at rt. In the case of the reactions with 9a and 9b, the conversion was complete after 1

HETEROCYCLES, Vol. 86, No. 1, 2012
353
h. The solvent was removed under vacuum, and the residue was purified on preparative TLC plates (SiO2)
using hexane/AcOEt (1:4) to give 13a – c as more polar fractions (Rf ~ 0.2). In all cases, the less polar
fraction ((Rf ~ 0.8) was isolated and indetified as methyl prolinate (14b).
The reaction of 16 with 1b, carried out in EtOH solution, was complete only after 16 h, and after
evaporation of the solvent, crude products were separated on preparative TLC plates (SiO2) using
hexane/AcOEt (1:4). In this case, 13b was isolated as a the less polar fraction and imidazolone (17) from
a fraction located near the start line. After eluation and evaporation of the solvent, the isolated material
was identified by comparison of its 1H NMR with a literature sample.14
Diethyl 3-amino-1H-pyrazole-4,5-dicarboxylate (13a). Yield: 169 mg (80%). Colorless solid, mp
93!96 °C (MeOH). IR (KBr): 3363m (NH), 3290s (NH), 2983m, 1717vs (C=O), 1684vs (C=O), 1619m,
1520m, 1305m, 1254m, 1131m, 1050m. 1H-NMR (CDCl3): 6.13 (br.s, NH2); 4.41, 4.29 (2q, J = 7.2 Hz, 2
13
MeCH2); 1.39, 1.34 (2t, J = 7.2 Hz, MeCH2). C-NMR (CDCl3): 164.5, 142.8, 93.5 (3 arom. C); 163.7,
153.0 (2 C=O); 61.9, 59.8 (2 MeCH2); 14.4, 14.1 (2 MeCH2). HR-ESI-MS (MeCN+NaI): 250.07958
(calcd. 250.07983 for C9H13N3NaO4, [M+Na]+).
Dimethyl 3-amino-1H-pyrazole-4,5-dicarboxylate (13b). Yield: 81 mg (44%). Colorless solid, mp
163!166 °C (MeOH). IR (KBr): 3281s (NH), 2958m, 1730vs (C=O), 1697vs (C=O), 1625m, 1524m,
1
13
1254m, 1130m. H-NMR (CDCl3): 6.10 (br.s, NH2); 3.94, 3.83 (2s, 2 MeO). C-NMR (CDCl3): 164.6,
142.5, 93.5 (3 arom. C); 163.8, 152.9 (2 C=O); 52.6, 51.2 (2 MeO). HR-ESI-MS (MeCN+NaI):
222.04834 (calcd. 222.04853 for C7H9N3NaO4, [M+Na]+).
Diisopropyl 3-amino-1H-pyrazole-4,5-dicarboxylate (13c). Yield: 132 mg (56%). Colorless solid, mp
182!185 °C (MeOH). IR (KBr): 3326m (NH), 3281s (NH), 2981m, 1713vs (C=O), 1680vs (C=O), 1625m,
1520m, 1300m, 1100m, 1032m. 1H-NMR (CDCl3): 6.10 (br.s, NH2); 5.27!5.20 (m, 2 CH); 1.39, 1.34 (2d,
13
J = 6.6, 4 Me). C-NMR (CDCl3): 164.2, 143.0, 93.7 (3 arom. C); 163.2, 152.9 (2 C=O); 70.1, 67.3 (2
CH); 22.2, 21.8 (4 Me). HR-ESI-MS (MeCN+NaI): 278.11129 (calcd. 278.11113 for C11H17N3NaO4,
[M+Na]+).
Ethyl 1-benzyl-2,3-dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxylate (17). Yield: 0.143 g (55%).
Colorless crystals, mp 195–198 °C (MeOH, lit.,14 194–198 °C, CH2Cl2/Et2O). 1H-NMR (CDCl3): 9.70 (br.
s, NH); 7.37–7.21 (m, 5 arom. H); 4.91 (s, PhCH2); 4.28 (q, J = 7.1 Hz, MeCH2); 2.29 (s, Me); 1.32 (t, J =
7.1 Hz, MeCH2).

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Three-component reaction of 9a, 1b and 3-(4-fluorophenyl)-2,2-dimethyl-1-azabicyclo[1.1.0]butane
(15). To a solution of hydrazide (9a, 1 mmol) and 1520 (1 mmol) in 1 mL of MeOH, 1 mmol of
dicyanofumarate (1b) was added. The mixture was stirred for 1 h at rt, the solvent was evaporated under
vacuum, and the residue was purified on preparative TLC plates (SiO2) using hexane/AcOEt mixture
(1:4) to give 13b. Yield: 138 mg (69%).
X-Ray Crystal-Structure Determination of 11a (Figures 1 and 2).21 All measurements were made on a
Agilent Technologies SuperNova area-detector diffractometer22 using CuK! radiation (! = 1.54184 Å)
from a micro-focus X-ray source and an Oxford Instruments Cryojet XL cooler. Data reduction was
performed with CrysAlisPro.22 The intensities were corrected for Lorentz and polarization effects, and an
empirical absorption correction using spherical harmonics22 was applied. The space group was determined
from packing considerations, a statistical analysis of intensity distribution, and the successful solution and
refinement of the structure. Equivalent reflections, other than Friedel pairs, were merged. The data
collection and refinement parameters are given below. A view of the molecule is shown in Figure 1 and
the packing diagram in Figure 2. The structure was solved by direct methods using SHELXS97,23 which
revealed the positions of all non-H-atoms. There are two molecules in the asymmetric unit whose
conformations differ by slightly different puckering of the six-membered ring and a significantly different
orientation of the terminal ester methyl group. The non-H-atoms were refined anisotropically. The amine
H-atoms were placed in the positions indicated by a difference electron density map and their positions
were allowed to refine together with individual isotropic displacement parameters. All remaining
H-atoms were placed in geometrically calculated positions and refined by using a riding model where
each H-atom was assigned a fixed isotropic displacement parameter with a value equal to 1.2U of its
eq
2
parent C-atom (1.5U for the methyl group). The refinement of the structure was carried out on F by
eq
using full-matrix least-squares procedures, which minimized the function "w(Fo2–Fc2)2. A correction for
secondary extinction was applied. Neutral atom scattering factors for non-H-atoms were taken from ref.24,
and the scattering factors for H-atoms were taken from ref.25 Anomalous dispersion effects were included
in F ;26 the values for ƒ’ and ƒ” were those of ref.27 The values of the mass attenuation coefficients are
c
those of ref.28 All calculations were performed using the SHELXL97 program.23 Crystal data for 11a:
Crystallized from hexane/CH2Cl2, C12H15N3O3, M = 249.27, pale yellow, tablet, crystal dimensions 0.09 "
0.20 " 0.20 mm, triclinic, space group P1, Z = 2, reflections for cell determination 5029, 2# range for cell
determination 12–153°, a = 7.3920(3) Å, b = 7.4342(3) Å, c = 11.7274(5) Å, $ = 98.503(3), % =
98.135(3)°, & = 103.850(4), V = 608.25(4) Å3, DX = 1.361 g#cm–3, µ(CuK$) = 0.830 mm–1, T = 160(1) K, '
scans, 2#max = 153.2°, transmission factors (min; max) 0.738; 1.000, total reflections measured 6237,
symmetry independent reflections 3907, reflections with I > 2((I) 3875, reflections used in refinement

HETEROCYCLES, Vol. 86, No. 1, 2012
355
3907, parameters refined 336, restraints 3, final R(F) (I > 2((I) reflections) = 0.0337, wR(F2) (all data) =
0.1048 (w = [(2(Fo2) + (0.0576P)2 + 0.1927P]–1 where P = (Fo2 + 2Fc2)/3, goodness of fit 1.128, final
)max/( = 0.001, )* (max; min) = 0.28; –0.19 e Å–3.
ACKNOWLEDGEMENTS
We thank the analytical services of our institute for NMR spectra and PD Dr. L. Bigler, University of
Zurich, for HR-ESI-MS. A. M. P. is grateful for financial support within the project European Social
Fund ‘HUMAN – BEST INVESTMENT!’, co-funded by the European Union. Skilful help by Mrs.
Ma#gorzata Celeda in performing of some experiments is acknowledged.
REFERENCES AND NOTES
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