The Synthesis of Various 2-Imino-2H-chromene-3-carbonitrile Derivatives †

: One-pot and stepwise reactions of salicylic aldehydes (salicylic, 5-bromsalicylic) and different equivalents of malononitrile and their mutual transformations were investigated. Various derivatives of 2-imino-2H-chromene-3-carbonitrile were isolated. This work reports the synthesis of novel 2-(4-amino-9-R-1-cyano-5-imino-3,5-dihydro-2H-chromeno[3,4-c]pyridin-2-ylidene)malononitriles. The inﬂuence of reaction parameters, such as ultrasound activation conditions, solvent type, and the presence or absence of a catalyst, was studied in this work. The structures of the synthesized compounds were established using spectroscopic data (IR, NMR).


Introduction
Heterocyclic-fused derivatives of imino(amino)chromenes of natural and synthetic origin exhibit a wide variety of biological properties including antimicrobial, antiviral, anticancer, antioxidant, and anti-inflammatory activities [1][2][3].Also, imino(amino)chromene derivatives have great interest in the fundamental research of organic chemistry.

Results and Discussion
In this work, we investigated the mutual transformations of imino(amino)cyanochromenes 1 and 2, as well as the accompanying reactions leading to previously unknown compounds.It has been shown that reactions of salicylic aldehyde and malononitrile with a 1:1 ratio in various solvents (IPA, EtOH, THF, dioxane, PEG-400) under thermal and ultrasound activation conditions, or with stirring at room temperature, can lead to the formation of 1, 2, 3 and 4 (Scheme 1).These reactions can occur with the presence of basic catalysts or under catalyst-free conditions.

Scheme 1.
Reactions between salicylaldehyde and malononitrile for the synthesis of imino(amino)cyanochromenes derivatives.The 1 H NMR spectra of the tautomers 3b and 3b' (R = Br) showed characteristic signals of doublets at 4.8-4.9ppm for the vicinal protons H 1 -H 10b (3b and 3b ) and singlets at 7.1, 6.72 (3), 6.53, and 6.34 ppm (3 ) for the amino groups and at 3.65 ppm (3 ) for the imino group.The two-dimensional 1 H/ 13 C HSQC spectrum of 3b and 3b displayed correlations between the vicinal protons H 1 and H 10b and the sp3-hybridized carbon atoms C 1 and C 10b , respectively: 4.9/34.89(H 1 /C 1 ), 4.88/30.82(H 10b /C 10b ).The two-dimensional 1 H/ 13 C HMBC spectrum contains cross peaks showing the main correlations for the two tautomers 3b and 3b (R = Br  Previously, compounds 2 and 3 were obtained using a 1:2 or 1:3 ratio of salicylic aldehydes and malononitrile, without taking into account the retro-Michael reaction, the possibility of the elimination of the malononitrile molecule from already formed molecules of aminochromene 2 [6][7][8]. Our study also showed that the reactions of equimolar amounts of salicylic aldehydes and malononitrile under ultrasound activation conditions without a catalyst led to the formation of 2-amino-6-R-4-((6-R-3-cyano-2H-chromen-2-ylidene)amino)-4H-chromene-3carbonitriles 5a,b (R = H, Br), which are the dimers of 2-iminochromene 1 (Scheme 3).The subject dimers have been synthesized previously [4] via stirring in methanol and water, in the presence of triethylamine at room temperature for 6-20 h.We observed the formation of these dimers under catalyst-free conditions in higher yields within a shorter reaction time.A dimeric compound 5b (R = Br) was synthesized for the first time.The authors of references [4][5][6][7][8][9][10][11][12][13] described how the domino reactions of salicylic aldehydes with one, two, and three molecules of malononitrile led to the formation of 2-iminochromene 1 derivatives depending on the reaction conditions and reaction time.We have shown the formation of dimers during one-pot reactions of salicylic aldehydes with molecule of malononitrile.
Thus, salicylic aldehydes and malononitrile undergo a wide range of transformations, among which the most important are the retro-Michael reaction, oxidation processes, and dimerization processes.

General Information, Instrumentation, and Chemicals
The IR spectra were recorded on an FSM 1201Fourier spectrometer in KBr pellets.The 1 H, 13 C, 1 H/ 13 C HSQC, 1 H/ 1 H COSY, and 1 H/ 13 C HMBC spectra were recorded on a Varian 400 MHz spectrometer at 400 MHz (1H), the 13 C spectra were recorded at 100 MHz.NMR spectra were recorded in CDCl 3 , (CD 3 ) 2 CO, and DMSO-d6, internal standard TMS.Elemental analysis was performed on a Vario MICRO Cube automatic CHNS analyzer.The melting points were determined in an open capillary.The reaction progress was monitored by TLC on Fluka Silicagel/TLC-cards, eluent hexane-ethyl acetate-chloroform (2:2:1), and visualized by exposure to UV light and iodine vapor.Ultrasonic synthesis was performed in a Sapphire TTC ultrasonic bath (2.8 L, heated).(A) Equimolar amounts of malononitrile (0.13 g, 0.002 mol) and salicylic aldehyde (0.002 mol) were refluxed in dioxane for 6 h.The beige crystals that precipitated were filtered off, washed with hexane, and dried in desiccators.(B) 2a (0.3 g) was stirred in IPA at 60   •

Conclusions
In addition to the condensation reaction, retro-Michael reactions, oxidation processes, and dimerization processes occur in the reaction of malononitrile and salicylic aldehydes, which leads to new compounds 4a,b, and 5b.