A new approach to morpholin-2-one derivatives via the reaction of β -amino alcohols with dicyanofumarates

A novel approach for the synthesis of morpholin-2-one derivatives from dialkyl dicyanofumarates and  -amino alcohols is presented. The reaction takes place under mild conditions via an addition-elimination-lactonization pathway. The formation of the six-membered ring occurs selectively leading to a single diastereomer. In contrast to arylhydrazines, the reaction of hydrazine hydrate with dicyanofumarates yields pyrazol-3(2 H )-ones and not 5-aminopyrazoles.


Introduction
The electron-deficient dicyanofumarates 1 are known as excellent dienophiles, 2 dipolarophiles, 3 and Michael acceptors. 4In the case of cycloaddition reactions, esters 1 as well as the stereoisomeric dicyanomaleates were used as a pair of substrates for the determination of the concertedness of these processes.2a,3a Reactions of dimethyl dicyanofumarate (1a) with ammonia, primary and secondary amines occur smoothly at room temperature according to the addition/elimination mechanism leading to 'push-pull' enamines of type 2 (Scheme 1).
Both ethylenediamine and trans-cyclohexane-1,2-diamine react with different dialkyl dicyanofumarates 1 yielding the corresponding piperazin-2-one derivatives of type 6. 5 For example, diethyl dicyanofumarate (1b) and ethylenediamine react via the initiating step leading to enamine 5, which has never been isolated and characterized.Under the reaction conditions, 5 undergoes spontaneous lactamization to give exclusively piperazin-2-one derivative 6a (Scheme 2). 5 EtO Scheme 2. Reaction of diethyl dicyanofumarate (1b) with ethylenediamine. 5nother group of nitrogen di-nucleophiles used in reactions with 1 are arylhydrazines.The reactions in ethanol in the presence of sodium or ammonium acetate also occur stepwise leading to 5-aminopyrazole-3,4-dicarboxylates 7 (Scheme 3).Apparently, the initially formed enehydrazine intermediate undergoes a cyclization via nucleophilic attack onto the cyano group.The alternative lactamization was not observed.To the best of our knowledge, reactions of 1 with other di-nucleophiles like -amino alcohols or 1,2-diols, which potentially can lead to morpholine and 1,4-dioxane derivatives, respectively, have not been reported yet.The goal of the present study was the examination of the reaction of selected -amino alcohols with dialkyl dicyanofumarates 1.

Results and Discussion
As an introductory experiment, diethyl dicyanofumarate (1b) was reacted with an equimolar amount of ethylenediamine in dichloromethane at room temperature with the aim of testing the reaction conditions. 5The already described piperazinone 6a 5 was isolated as the sole product in 51% yield.The structure is well confirmed by spectroscopic data.For example, in the 1 H-NMR spectrum, two broad NH absorptions are located at 7.39 and 10.18 ppm.The latter signal is attributed to the enamine NH group and correlates with earlier published data for a similar class of enamines.4b Two C=O absorptions appear at 1698 and 1659 cm -1 in the IR spectrum (KBr) and at 169.1 and 157.8 ppm in the 13 C-NMR spectrum.
In an analogous experiment with 1a and 2-aminoethanol (8a), the progress of the reaction was monitored by 1 H-NMR spectroscopy.In the spectrum registered after 30 min, only traces of both the starting material 1a and the expected product 10a could be detected.The major compound was characterized by two MeO absorptions at 3.98 and 3.79 ppm, indicative for the enamine intermediate 9a (R = Me, R 1 -R 4 = H; cf.enamines of type (Z)-2 4b ).After 16 h, the lactonization of enamine 9a was complete and morpholinone 10a was isolated in 49% yield (Scheme 4, Table 1).
Similar to the spectroscopic data of 6a, the obtained product 10a displays two C=O absorptions (IR: 1750 and 1678 cm -1 , 13 C-NMR: 168.2 and 157.5 ppm).On the other hand, the 1 H-NMR spectrum reveals the presence of only one NH signal at 10.28 ppm.These data indicate that the exocyclic C=C bond is (Z)-configured in accordance with the spectroscopic data of structurally similar 'push-pull' enamines of type 2. 4b The formation of the morpholinone derivative 10a can be rationalized in analogy to the formation of 6a (Scheme 2).The attack of the more nucleophilic NH2 group of β-aminoethanol (8a) onto 1, followed by elimination of HCN, leads to the proposed intermediate 9a (Scheme 4).Then, the less nucleophilic OH group reacts selectively with the 'geminal' ester group yielding the six-membered lactone 10a exclusively.
Based on the general protocol, a series of morpholinone derivatives 10a-10i was prepared using differently substituted β-amino alcohols 8 and some dialkyl dicyanofumarates 1 (Table 1).In all cases, the reactions were performed in dichloromethane at room temperature, and the isolation of the products was achieved by fractional crystallization.Attempted chromatographic separations led to decomposition of the products.In all cases, only one product was obtained.In the case of 10f, crystals suitable for an X-ray crystal structure determination were obtained, and the postulated (Z)-configuration of the exocyclic C=C bond was unambiguously confirmed (Figure 1).
The molecule is located on a crystallographic mirror plane, which results in disorder across the mirror plane of the methyl group and its adjacent C-atoms of the heterocyclic ring.The amine H-atom forms bifurcated hydrogen bonds, one arm of which is an intramolecular interaction with the ester carbonyl O-atom, while the other is an intermolecular interaction with the cyano N-atom of an adjacent molecule.The latter interaction links the molecules into extended chains which run parallel to the [100] direction and which can be described by a graph set motif 8 of C(6).In recent papers we described the preparation of 3-amino-1,1,1-trifluoro-2-arylpropan-2ols. 9Due to the importance of fluorinated systems, we decided to test the reaction of 1b with 3amino-1,1,1-trifluoro-2-phenylpropan-2-ol (8, R 1 = Ph, R 2 = CF3, R 3 = R 4 = H).Under standard conditions, the reaction stopped at the stage of the enamine 9j (R 1 = Ph, R 2 = CF3, R 3 = R 4 = H), and no lactonization occurred after heating of the reaction mixture.Even after replacement of dichloromethane by 1,2-dichloroethane or ethanol and heating to reflux for several hours, no morpholinone was obtained.We propose that the reduced nucleophilicity of the OH group in 9j is caused by the electron-withdrawing effect of the -trifluoromethyl group.In addition, the presence of a Ph and CF3 group in the -position of the alcohol increases the steric hindrance of the lactonization.
In an extension of the study with -amino alcohols, reactions of hydrazine hydrate with different dialkyl dicyanofumarates 1 were performed in ethanol at room temperature.In the cases of 1a and 1b, the reactions were complete within 15 min, and after crystallization, colorless solid products were isolated in good yields.In both cases, the 1 H-NMR spectra confirmed the presence of only one ester group.On the other hand, two signals from C=O groups appeared in the 13 C-NMR spectra.For example, the product obtained from 1a showed them at 168.4 and 162.2 ppm.According to 13 C-NMR and IR spectra, both compounds possess a cyano group.Based on these data, the structures were identified as pyrazol-3(2H)-one derivatives 12a and 12b, respectively (Scheme 5). 10 The proposed reaction pathway is presented in Scheme 5.In analogy to amines and β-amino alcohols, the initial attack of hydrazine onto the activated C=C bond, followed by elimination of HCN, affords ene-hydrazines 11a-11c, and subsequent nucleophilic attack of the NH2 group onto the 'vicinal' ester function yields 12.This mechanism found additional support by the isolation of 11c (R = iPr), obtained as a stable compound in the reaction with diisopropyl dicyanofumarate (1c).Two other derivatives, 11a and 11b, spontaneously undergo cyclization at room temperature yielding 12a and 12b, respectively.The observation that no cyclization of 11c to 12c occurs under the applied reaction conditions points to steric factors preventing the attack onto the ester group in this case.
In view of the reported results presented in Scheme 3, the formation of pyrazolones 12 (and not 5-aminopyrazoles 7) is a surprising observation.A reasonable explanation is based on the assumption that 11 is formed as the (Z)-isomer, whereas in the case of arylhydrazines the intermediate ene-hydrazine is (E)-configured.A likely reason for the formation of different stereoisomers of ene-hydrazines is of steric origin, and in the case of N-aryl substituted derivatives, the elimination of HCN from the initially formed adduct yields preferentially the (E)-configured ene-hydrazine.

Conclusions
The results described in this paper show that dialkyl dicyanofumarates 1 can be used as building blocks for the preparation of functionalized morpholin-2-ones 10 upon treatment with -amino alcohols.This new method extends known protocols for the synthesis of morpholine derivatives.
Taking into account that both dicyanofumarates and -amino alcohols are easily available starting materials, this method can be applied successfully for the regioselective synthesis of a variety of morpholin-2-one derivatives.The importance of morpholinones and other morpholine derivatives as biologically relevant substances is well documented. 11Unexpectedly, the reactions of dicyanofumarates with hydrazine hydrate lead to pyrazolones and not to aminopyrazoles, as reported for the reactions with arylhydrazines.Whereas in the case of the reaction with hydrazine an ester group is involved in the cyclization, it is the cyano group in the case of arylhydrazines.

Experimental Section
General.Melting points were determined in a capillary using a Melt-Temp.II apparatus (Aldrich) or STUART SMP30 and are uncorrected.The IR Spectra were recorded on a NEXUS FT-IR spectrophotometer in KBr; absorptions (υ) in cm -1 .The 1 H-(600 MHz), 13 C{ 1 H}-(150 MHz) and 19 F-NMR (565 MHz) spectra were measured on a Bruker Avance III instrument using solvent signals as reference.Chemical shifts (δ) are given in ppm and coupling constants J in Hz.Assignments of signals in 13 C-NMR spectra were made on the basis of HMQC experiments.HR-MS: Bruker Esquire LC spectrometers.All solvents are commercially available reagents and used as received.Dimethyl-, diethyl-and diisopropyl dicyanofumarates 1a-1c were prepared from corresponding cyanoacetates by treatment with pure thionyl chloride according to the published general procedure. 12Attention: reaction could be performed successfully only when the commercial thionyl chloride was purified by distillation over quinoline and linseed oil following the recommended procedure. 13

X-Ray Crystal Structure Determination of 10f
All measurements were made on an Oxford Diffraction SuperNova area-detector diffractometer 14 using MoK radiation ( = 0.71073 Å) and an Oxford Instruments Cryojet XL cooler.Data reduction was performed with CrysAlisPro. 14The intensities were corrected for Lorentz and polarization effects, and an absorption correction based on the multi-scan method 14 was applied.The space group was determined from the systematic absences, packing considerations, a statistical analysis of intensity distribution, and the successful solution and refinement of the structure.Equivalent reflections were merged.The data collection and refinement parameters are given below.A view of the molecule is shown in the Figure .The structure was solved by direct methods using SHELXS97, 15 which revealed the positions of all non-hydrogen atoms.The molecule is located on a crystallographic mirror plane, which results in equal occupancy disorder across the mirror plane of the methyl group and its adjacent C-atoms of the heterocyclic ring.The non-hydrogen atoms were refined anisotropically.The amine H-atom was placed in the position indicated by a difference electron density map and its position was allowed to refine together with an isotropic displacement parameter.This H-atom is also disordered across the mirror plane.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 F 2 by using full-matrix least-squares procedures, which minimized the function w(Fo 2 -Fc 2 ) 2 .A correction for secondary extinction was applied.
Neutral atom scattering factors for non-hydrogen atoms were taken from ref. 16a , and the scattering factors for hydrogen atoms were taken from ref. 17 .Anomalous dispersion effects were included in Fc (ref. 18); the values for f' and f" were those of ref. 16b .The values of the mass attenuation coefficients are those of ref. 16c .The SHELXL97 program 19 was used for all calculations.Crystallographic data for compound 10f. 20

Figure 1 .
Figure 1.ORTEP plot 7 of the molecular structure of 10f (arbitrary numbering of the atoms, 50% probability ellipsoids).The alternative conformation of the disordered ring is not shown.