HETEROCYCLES

Paper | Special issue | Vol. 86, No. 1, 2012, pp. 343-356
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 Mlostoń,* Adam M. Pieczonka, Aneta Wróblewska, Anthony Linden, and Heinz Heimgartner*

Institute of Organic Chemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland

Abstract

The reaction of prolinamine derivatives (8a,b) and dialkyl dicyanofumarates (1) in dichloromethane at room temperature leads to the optically active enamines of type (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 dicyanofumarates (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 β-amino alcohols (2), the reaction occurs stepwise and, after initial formation of the β-hydroxyalkylenamine (3), subsequent cyclocondensation affords morpholinone derivatives (4)6 (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).

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]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 proposed (Z)-configuration of 10b is supported by 1H- and 13C-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.

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).

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 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 attributed to the C=C bond of the ‘push-pull’ enehydrazine structure.4 The 1H-NMR spectrum indicates the presence of two MeO groups, with absorptions at 3.95 and 3.81 ppm, and the N-benzylpyrrolidine moiety.

In order to examine cyclization reaction of compound 12b, a sample of 12b was dissolved in commercial CDCl3 (for the NMR usage) and was periodically controlled by 1H-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 only three signals in the 1H-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 m/z 222.04834 corresponding with the molecular formula C7H9N3O4. In addition, the 13C-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 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

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 room temperature, the 1H-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 amount of 1b in methanolic solution. After 1 h, the reaction was complete, and the 1H-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 9a, 1b, and 3-(4-fluorophenyl)-2,2-dimethyl-1-azabicyclo[1.1.0]butane (15) was carried out in methanol at room temperature. The 1H-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.

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.

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.

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 (υ) 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 shifts (δ) are given in ppm and coupling constants J in Hz. Assignments of signals in 13C-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 λ = 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: 220 mg (57%). Pale yellow oil. [α]D20 –135 (c 0.4, CH2Cl2). IR (film): v 3226m, 2978m, 2211s (CN), 1746s (C=O), 1674s, 1588s, 1274m, 1044m, 785m. 1H-NMR (CDCl3): δ 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); 1.33 (t, JH,H = 7.2 Hz, 3H, MeCH2). 13C-NMR (CDCl3): δ 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).
Yield: 283 mg (79%). Pale yellow oil. [α]D20 –133 (c 1.0 CH2Cl2). IR (film): v 3228m, 2954m, 2211s (CN), 1748s (C=O), 1680s, 1589s, 1281m, 1045m, 796m. 1H-NMR (CDCl3): δ 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 (m, 2H, H2C(4’)); 1.66–1.59 (m, 1H, HC(3’)). 13C-NMR (CDCl3): δ 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. [α]D20 –135 (c 0.4 CH2Cl2). IR (film): v 3223m, 2980m, 2211s (CN), 1743s (C=O), 1668s, 1588s, 1277m, 1100m, 700m. 1H-NMR (CDCl3): δ 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 Me2CH). 13C-NMR (CDCl3): δ 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 (11a). Yield: 198 mg (79%). Pale yellow crystals, mp 213–214 °C (CH2Cl2/hexane). [α]D20 +534 (c 1.0 CH2Cl2). IR (KBr): v 3443m, 3208m, 2204s (CN), 1664s (C=O), 1585s, 1243s, 1174s, 796m. 1H-NMR (CDCl3): δ 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): δ 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 (11b). Yield: 152 mg (64%). Pale yellow crystals, mp 240–242 °C (decomp., CH2Cl2/hexane). [α]D20 +294 (c 1.0 CH2Cl2). IR (KBr): v 3439m, 3211m, 2210s (CN), 1663s (C=O), 1592s, 1252s, 1194s, 797m. 1H-NMR (CDCl3): δ 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, HC(7’)); 1.96–1.87 (m, 1H, HC(7’)); 1.69–1.61 (m, 1H, HC(8’)). 13C-NMR (CDCl3): δ 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-cyanoacetate (11c). Yield: 196 mg (74%). Pale yellow crystals, mp 200–202 °C (CH2Cl2/hexane). [α]D20 +507 (c 1.0 CH2Cl2). IR (KBr): v 3442m, 2983m, 2209s (CN), 1675s (C=O), 1601s, 1253s, 1110s, 770m. 1H-NMR (CDCl3): δ 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): δ 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-enedioate (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). [α]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 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 MeCH2); 1.39, 1.34 (2t, J = 7.2 Hz, MeCH2). 13C-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, 1254m, 1130m. 1H-NMR (CDCl3): 6.10 (br.s, NH2); 3.94, 3.83 (2s, 2 MeO). 13C-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, J = 6.6, 4 Me). 13C-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).

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 CuKα radiation (λ = 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 1.2Ueq of its parent C-atom (1.5Ueq for the methyl group). The refinement of the structure was carried out on F2 by using full-matrix least-squares procedures, which minimized the function Σw(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 Fc;26 the values for ƒ’ and ƒ” were those of ref.27 The values of the mass attenuation coefficients are 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, 2θ range for cell determination 12–153°, a = 7.3920(3) Å, b = 7.4342(3) Å, c = 11.7274(5) Å, α = 98.503(3), β = 98.135(3)°, γ = 103.850(4), V = 608.25(4) Å3, DX = 1.361 g⋅cm–3, µ(CuKα) = 0.830 mm–1, T = 160(1) K, ω scans, 2θmax = 153.2°, transmission factors (min; max) 0.738; 1.000, total reflections measured 6237, symmetry independent reflections 3907, reflections with I > 2σ(I) 3875, reflections used in refinement 3907, parameters refined 336, restraints 3, final R(F) (I > 2σ(I) reflections) = 0.0337, wR(F2) (all data) = 0.1048 (w = [σ2(Fo2) + (0.0576P)2 + 0.1927P]–1 where P = (Fo2 + 2Fc2)/3, goodness of fit 1.128, final Δmax/σ = 0.001, Δρ (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. Małgorzata Celeda in performing of some experiments is acknowledged.

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