Reactions of New N-(2,2-Dichloro-1-cyanoethenyl)amides with Aliphatic Amines

The reaction of the newly synthesized N-(2,2-dichloro-1-cyanoethenyl)prop-2-enamide and 4-chloro-N-(2,2-dichloro-1-cyanoethenyl)butanamide with methylamine or dimethylamine gave rise to previously unknown 5-amino-1,3-oxazole-4-carbonitriles. In the case of the reaction of N-(2,2-dichloro-1-cyanoethenyl)amides with ethylenediamine diacetate, new (Z)-2,3,5,6,7,8-hexahydro-7-oxo-1H-imidazo[1,2-a][1,4]diazepine-9-carbonitrile and 4-chloro-N-(cyano(imidazolidin-2-ylidene)methyl)butanamide were obtained.

The reaction of N-(2,2-dichloro-1-cyanoethenyl)-4-chlorobutylamide 3 with dimethylamine proceeded similarly to compound 2. In this case, 5-(dimethylamino)-2-[3-(dimethylamino)propyl]-1,3-oxazole-4-carbonitrile 7 was formed in high yield (Scheme 3). Substituted 5-amino-1,3-oxazole-4-carbonitrile 8 containing a chloropropyl residue in the second position of the ring was isolated, when using an excess of methylamine. Probably, the substitution of the chlorine atom in the chloropropyl residue was not observed due to the lower nucleophilicity of methylamine as compared to dimethylamine. The reaction of ethylenediamine diacetate with nitrile 3 led to the formation of ketenaminal 9, which was isolated in the acetate form. Attempts to carry out targeted intramolecular alkylation of the ketenaminal moiety with a chloropropyl residue in order to obtain a bicyclic structure 10 were unsuccessful. Structure and purity of the obtained compounds were proved by the liquid chromatography-mass spectrometry, IR spectroscopy, elemental analysis, and NMR spectroscopy methods. Structure of compounds 4а and 6 was unambiguously confirmed by means of 2D NMR techniques (COSY, HSQC, HMBC) (Scheme 4). The presence in the 1 H NMR spectra of signals of aliphatic protons and NH-groups, as well as their multiplicity, make it possible to determine the corresponding fragments in the molecule of compound 4а. The protons of the methylene (2.75 ppm) and methyl (2.95 ppm) groups in the HMBC spectrum correlate with the C 2 and C 5 carbon atoms (152.1, 162.5 ppm), which is characteristic of the 5-aminooxazole fragment.
Structure of compound 6 is confirmed by the presence of the signal of an NH proton at 8.30 ppm in the 1 H NMR spectrum. The fact that the NH group is directly bonded to the carbon atom at the nitrile group (59.2 ppm) is confirmed by HMBC correlations. Also, the protons of the CH 2 groups of the diazepine ring in the HMBC spectrum correlate with the carbon atom of the carbonyl group (172.37 ppm). The interaction of protons of two methylene groups (3.31 and 3.42 ppm), as well as one NH-proton with a carbon atom at a double bond (158.2 ppm) indicates the formation of (Z)-2,3,5,6,7,8hexahydro-7-oxo-1H-imidazo[1,2-a] [1,4]diazepine ring.
In summary, we first studied the reactions of N- ( EXPERIMENTAL IR spectra were recorded on a Vertex-70 spectrometer from KBr pellets. 1 H and 13 C NMR spectra were taken on a Bruker AVANCE DRX-500 instrument (500 and 125 MHz, respectively) from DMSO-d 6 or CDCl 3 solution. Chromato-mass spectra were recorded using a liquid chromatography-mass spectrometry system on an Agilent 1100 Series high performance liquid chromatograph equipped with an Agilent LC\MSD SL mass selective detector diode array. Chromatographymass analysis parameters: column Zorbax SB-C18 1.8 μm 4.6 × 15 mm (PN 821975-932); solvents: А, MeCN-H 2 O, 95 : 5, 0.1% TFA; B, 0.1% aqueous TFA; eluent flow 3 mL/min; injection volume 1 μL; UV detectors: 215, 254, 285 nm; ionization method was atmospheric pressure chemical ionization (APCI), scanning range m/z 80-1000 Da. Elemental analysis was performed in the analytical laboratory of the V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine. The content of carbon and hydrogen was determined by the Pregl gravimetric method, nitrogen-by the Dumas gas-metric micromethod, and chlorine-by the Schöniger titrimetric method [11]. Melting points were measured on a Fisher-Johns apparatus. The reaction progress and the purity of the obtained compounds were monitored by thin layer chromatography on Macherey-Nagel ALUGRAM Xtra SIL G/UV254 plates in the chloroform-methanol system (10 : 0.2).

N -(2,2-Dichloro-1-cyanoethenyl)prop-2enamide (2) and N-(2,2-dichloro-1-cyanoethenyl)-4chlorobutylamide (3)
were obtained by the previously described method [6]. To a solution of 13.7 g (100 mmol) of 2-amino-3,3-dichloroacrylonitrile 1 and 12.1 g (100 mmol) of N,N-dimethylaniline in 100 mL of diethyl ether with vigorous stirring was added dropwise the corresponding acid chloride (100 mmol) at 20-25°C. The resulting mixture was stirred for 12 h, then 200 mL of a water-hexane mixture (1 : 1) was added. A precipitate formed in the two-phase system was filtered off, washed with 50 mL of a hexane-diethyl ether mixture (1 : 1), and dried in a vacuum. Compounds 2, 3 were used for further transformations without additional purification .  N-(2,2-Dichloro-1-cyanoethenyl) nitriles (4а, 4b). To a solution of 10 mmol of compound 2 in 20 mL of methanol with vigorous stirring was added 10 mL of a 40% aqueous solution of dimethylamine or 20 mL of a 20% methanol solution of methylamine at 20-25°С. The solution was stirred for 48 h, the excess of the corresponding amine, and the solvent was removed in vacuum at 40°С. A solution of 6.9 g (50 mmol) of K 2 CO 3 in 20 mL of water was added to the residue, and compound 4 was extracted with methylene chloride (3 × 30 mL). The extract was washed with water (4 × 5 mL) and dried with Na 2 SO 4 , the solvent was removed in vacuum. The obtained compounds were purified by flash chromatography, using a mixture CH 2 Cl 2 -methanol as eluent.

5-(Dimethylamino)-2-[3-(dimethylamino)propyl]-1,3-oxazole-4-carbonitrile (7)
. To a solution of 10 mmol of compound 3 in 20 mL of methanol with vigorous stirring was added 10 mL of a 40% aqueous solution of dimethylamine at 20-25°С. The solution was stirred for 48 h, an excess of amine and the solvent were removed in vacuum at 40°С. A solution of 6.9 g (50 mmol) of K 2 CO 3 in 20 mL of water was added to the residue and extracted with methylene chloride (3 × 30 mL). The extract was washed with water (4 × 5 mL) and dried with Na 2 SO 4 , the solvent was removed in vacuum.

4-Chloro-N-[cyano(imidazolidin-2-ylidene)methyl]butanamide (9).
To a solution of 7.2 g (40 mmol) of ethylenediamine diacetate in 20 mL of methanol 2.4 g (10 mmol) was added in portions (0.2 g each) with vigorous stirring compound 3 at 20-25°С. The reaction mixture was stirred for 48 h, and ethylenediamide hydrochloride was filtered off. The solvent was removed in vacuum at 40°С, then 20 mL of water was added to the residue, and the product was extracted with a mixture of СН 2 Cl 2 -propan-2-ol (8 : 2, 6 × 20 mL). The solvent was removed in vacuum, the residue was treated with 20 mL of propan-2-ol, and the crystals were filtered off to To obtain free base 9, 2 g of acetate was dissolved in 5 mL of water, and then 5 mL of a saturated aqueous solution of NaHCO 3 was added. The formed precipitate was filtered off, washed with water (2 × 3 mL) and dried in vacuum at 40°С. Yield 85%, mp 80-82°С.

CONFLICT OF INTEREST
No conflict of interest was declared by the authors.

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