The Heterocyclization of 2-Imino-2H-chromeno-3-carbonitriles with Some N,N-Binucleophiles ^†

Abstract

We investigated one-pot, three-component, and stepwise reactions of malononitrile and salicylic aldehydes (salicylic, 5-bromsalicylic) with N,N-nucleophiles, such as hydrazine hydrate, nitrobenzhydrazides, and o-phenylenediamine, under various conditions. This work reports on the synthesis of novel chromeno[4,3-c]pyrazoles and chromeno[4,3-e][1,4]diazepines. The influence of reaction parameters, such as solvent type and temperature, was studied. The structures of the synthesized compounds were established using spectroscopic data (IR, NMR).

1. Introduction

Fused heterocyclic chromene derivatives with chromenopyrazole or chromenodiazepine skeletons have a wide spectrum of biological activity, including antitumor [1,2], antimicrobial, antibacterial [2,3,4,5,6], antifungal [3], antioxidant [4,6], etc. Also, hybrid condensed chromene derivatives attract great interest in fundamental research on organic chemistry.

Previously, we described the preparation of new 2-imino-2H-chromeno-3-carbonitrile and 2-(2-amino-3-cyano-4H-chromen-4-yl)malononitrile derivatives via one-pot and stepwise reactions of salicylic aldehydes (salicylic, 5-bromsalicylic) and different equivalents of malononitrile [7]. This work is the continuation of studies on the preparation of new derivatives of 2-(2-amino-3-cyano-4H-chromen-4-yl)malononitrile using reactions with various N,N-binucleophiles. The possibility of synthesizing chromeno[4,3-c]pyrazoles and chromeno[4,3-e][1,4]diazepine under various conditions was studied in this paper.

2. Results and Discussion

The use of hydrazine hydrate, benzhydrazides of aromatic or heteroaromatic acids, or orthophenylenediamine as N,N-nucleophiles in three-component and stepwise reactions with malononitrile and salicylic aldehyde leads to the formation of new compounds of the chromeno[4,3-c]pyrazoles 1 and 2 and of the chromeno[4,3-e][1,4]diazepine 3 series (Scheme 1).

The novel 8-R-1,9b-dihydrochromeno[4,3-c]pyrazole-3,4-diamines (1a,b R = H, Br) were synthesized via a one-pot three-component reaction of malononitrile and salicylic aldehydes with unsubstituted hydrazine hydrates under magnetic stirring in isopropyl alcohol at 40 °C. Chromeno[4,3-c]pyrazoles 1 were similarly prepared by two-step reaction method: this involved the preliminary preparation of 6R-2-imino-2H-chromeno-3-carbonitrile A, and the subsequent introduction of substrate A into the reaction with hydrazine hydrate (Scheme 2).

The formation of chromeno[4,3-c]pyrazoles 1 proceeds according to the following scheme. Malononitrile and salicylic aldehyde undergo Knoevenagel condensation and intramolecular O-cyclization reactions in the presence of the basic catalyst triethylamine to form the intermediate 2-imino-2H-chromeno-3-carbonitrile A. Subsequently, new products (such as 1,9b-dihydrochromeno[4,3-c]pyrazole-3,4-diamine 1) are formed by the nucleophilic attack of hydrazine on 6R-2-imino-2H-chromeno-3-carbonitrile A and subsequent intramolecular cyclization.

The structure of 8-R-1,9b-dihydrochromeno[4,3-c]pyrazole-3,4-diamines (1a,b R = H, Br) was confirmed using IR and NMR spectroscopy data.

The ¹H NMR spectra of the 1a (R = H) and 1b (R = Br) (Figure 1) showed characteristic signals of singlets at 5.96 and 7.04 ppm (1a). These were seen at 6.67 and 7.33 ppm (1b) for the amino groups and at 11.32 ppm (1a) and 11.51 ppm (1b) for the imino group. These were seen at 6.34 ppm (1a) and 6.77 ppm (1b) for the methine proton H^9b. The two-dimensional ¹H/¹³C HSQC spectrum of 1a displayed correlations between the methine proton H^9b and the sp3-hybridized carbon atom C^9b, respectively: 6.34/47.98 (1a) and 6.77/50.86 (1b).

A three-component reaction of equimolar amounts of malononitrile, salicylic aldehyde, and hydrazides (isoniazid, 2-, 3-nitrobenzhydrazide) under boiling conditions in ethanol, dioxane, or THF in the presence of catalytic amounts of triethylamine predominantly leads to the formation of Schiff bases—N′-(2-hydroxybenzylidene)-hydrazides B [8]. A three-component reaction of malononitrile, salicylic aldehyde, and 3-nitrobenzhydrazide at room temperature using THF as a solvent leads to the formation of new (3,4-diimino-1,3a,4,9b-tetrahydrochromeno[4,3-c]pyrazol-2(3H)-yl)(3-nitrophenyl)methanone 2 (Scheme 3).

The ¹H NMR spectrum of (tetrahydrochromeno[4,3-c]pyrazolyl)(3-nitrophenyl)methanone 2 showed characteristic signals of doublet at 4.80 ppm and the doublet of doublets at 5.84 ppm for the vicinal protons H¹ and H², respectively, and also singlets at 7.80, 7.85, and 10.99 ppm for the imino groups (Figure 2).

The two-dimensional ¹H/¹³C HSQC spectrum of compound 2 displayed correlations between the vicinal protons H¹ and H² and the sp3-hybridized carbon atoms C¹ and C², respectively: 4.8/51.85 (H¹/C¹), 5.84/53.71 (H²/C²). The main correlations in the ¹H/¹³C HMBC spectrum are 4.81/53.70 (H¹/C²); 4.8/144.79 (H¹/C¹⁰); 4.8/163.35 (H¹/C¹⁶); 4.8/187.42 (H¹/C³); 5.84/51.85 (H²/C¹); and 5.84/187.42 (H²/C³) (Figure 3).

The stepwise reaction of 2-imino-2H-chromeno-3-carbonitrile between 3-nitrobenzhydrazide at room temperature in the THF similarly led to the formation of the target chromeno[4,3-c]pyrazole 2.

The proposed reaction mechanism is similar to that described above and includes initial Knoevenagel condensation to form an intermediate 6R-2-imino-2H-chromeno-3-carbonitrile A, as well as the subsequent nucleophilic attack of 3-nitrobenzhydrazide and heterocyclization to form product 2.

The heating of 2-imino-2H-chromeno-3-carbonitrile with benzhydrazides can lead to the formation of Schiff bases due to nucleophilic attacks by hydrazide, with the opening of the benzopyran ring and the elimination of malononitrile (Scheme 4). The effect of temperature on 2-imino-2H-chromeno-3-carbonitrile may also contribute to the ring-opening process. Reactions that lead to the opening of the benzopyran ring of 2-imino-2H-chromeno-3-carbonitrile or similar chromene derivatives during intense heating (or boiling) are described in the literature [9,10].

The reaction of 2-imino-2H-chromene-3-carbonitrile and orthophenylenediamine in isopropyl alcohol under ultrasonic activation conditions proceeds with the formation of new 13,13a-dihydrobenzo[b]chromeno[4,3-e][1,4]diazepine-6,7-diamine 3 (Scheme 5).

The structure 13,13a-dihydrobenzo[b]chromeno[4,3-e][1,4]diazepine-6,7-diamine 3 was confirmed using IR and NMR spectroscopy data.

The ¹H NMR spectra of 3 showed characteristic signals of singlets at 7.14 and 7.20 ppm for the amino groups and at 6.30 ppm for the imino group, and also at 6.49 ppm for the methine proton H¹ (Figure 4). The two-dimensional ¹H/¹³C HSQC spectrum of 3 displayed correlations between the methine proton H¹ and the sp3-hybridized carbon atoms C¹, respectively: 6.49/50.68 (H¹/C¹).

3. Experimental

3.1. General Information, Instrumentation, and Chemicals

The IR spectra were recorded on an FSM 1201Fourier spectrometer in KBr pellets. The 1H, 13C, 1H/13C HSQC, 1H/1H COSY, and 1H/13C HMBC spectra were recorded on a Varian 400 MHz spectrometer at 400 MHz (1H). The 13C spectra were recorded at 100 MHz. NMR spectra were recorded in CDCl3, (CD3)2CO, and DMSO-d6 using 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’s progress was monitored using TLC on Fluka Silicagel/TLC-cards and eluent hexane–ethyl ace-tate–chloroform (2:2:1), and visualized by exposure to UV light and iodine vapor. Ul-trasonic synthesis was performed in a Sapphire TTC ultrasonic bath (2.8 L, heated).

3.2. Synthesis and Characterization of the Compounds

• 1,9b-dihydrochromeno[4,3-c]pyrazole-3,4-diamine 1a

We stirred (A) 0.004 mol (0.26 g) of malononitrile, 0.004 mol of salicylic aldehyde, and 0.008 mol of hydrazine hydrate into isopropyl alcohol for 1 h at 40 °C. The precipitate formed is filtered off, washed with isopropyl alcohol, and dried in a vacuum. We stirred (B) 0.004 mol (0.82 g) of 2-imino-2H-chromene-3-carbonitrile and 0.008 mol of hydrazine hydrate into isopropyl alcohol for 1 h at 40 °C. The precipitate formed is filtered off, washed with isopropyl alcohol, and dried in a vacuum.

M.p. = 306–308 °C. Yellow crystals. Calculated, %: C, 59.40; H, 4.98; N, 27.71; O, 7.91. C₁₀H₁₀N₄O. Found, %: C 59.19; H 4.95; N 27.55. IR, ν, cm⁻¹: 3442, 3350, 3238, 3188 (NH); 3050(Ar-H); 2925 (Csp3-H); 1550 (C=C); 1157 (C-O-C). ¹H NMR (DMSO-d6), δ, ppm: 5.96 (-NH₂, s, 2H); 6.34 (H^9b, s, 1H), 7.04 (-NH₂, s, 2H), 7.09–7.64 (C₆H₄, m, 4H); 11.32 (NH, s, 1H). ¹³C NMR (DMSO-d6), Cδ, ppm: 47.98 (C^9b); 71.92 (C^3a); 116.68 (C⁶ Ar); 132.87 (C⁷ Ar); 124.55 (C⁸ Ar); 129.13 (C⁹ Ar); 147.10 (C^5a); 158.77 (C-NH₂); 165.30 (C-NH²). ¹H/¹³C HSQC (DMSO-d6), δ, ppm: 6.34/47.98 (H^9b/C^9b). Yield: 54.5% (A), 45% (B).

• 8-bromo-1,9b-dihydrochromeno[4,3-c]pyrazole-3,4-diamine 1b

We stirred (A) 0.004 mol (0.26 g) of malononitrile, 0.004 mol (0.8) of 5-bromsalicylic aldehyde, and 0.008 mol of hydrazine hydrate into isopropyl alcohol for 3 h at 40 °C. The precipitate formed is filtered off, washed with isopropyl alcohol, and dried in a vacuum. We stirred (B) 0.004 mol (1 g) of 6-bromo-2-imino-2H-chromene-3-carbonitrile and 0.008 mol of hydrazine hydrate into an ultrasonic bath in isopropyl alcohol at 40 °C for 3 h. The precipitate formed is filtered off, washed with isopropyl alcohol, and dried in a desiccator.

M.p. = 287–288 °C. Dark yellow crystals. Calculated, %: C, 42.73; H, 3.23; Br, 28.42; N, 19.93; O, 5.69. C₁₀H₉BrN₄O. Found, %: C, 42.85; H, 3.22; N, 20.08. ¹H NMR (Acetone-d6), δ, ppm: 6.67 (-NH₂, s, 2H), 6.77 (H^9b, s, 1H), 7.25 (ArH⁶, d, 1H. J = 6.9 Hz), 7.33 (-NH₂, s, 2H), 7.79 (ArH⁷, d, 1H. J = 7.0 Hz,), 7.96 (ArH⁹, s, 1H,), 11.51 (NH, s, 1H). ¹³C NMR (Acetone-d6), Cδ, ppm: 50.86 (C^9b); 64.13 (C^3a); 116.21 (C⁸); 119.59 (C⁶ Ar); 134.66 (C⁷ Ar); 142.15 (C⁹ Ar); 151.46 (C^5a); 158.89 (C-NH₂); 160.55 (C-NH²). ¹H/¹³C HSQC (Acetone-d6), δ, ppm: 6.77/50.86 (H^9b/C^9b); 7.24/119.59 (H⁶/C⁶); 7.79/134.66 (H⁷/C⁷); 7.96/142.15 (H⁹/C⁹).

• Yield: 69% (A), 75% (B).

• (3,4-diimino-1,3a,4,9b-tetrahydrochromeno[4,3-c]pyrazol-2(3H)-yl)(3-nitrophenyl)methanone 2

(A) Equimolar amounts of malononitrile 0.002 mol (0.13 g,), salicylic aldehyde (0.002 mol) and 3-nitrobenzhydrazide 0.002 mol (0.36 g,) were stirred into THF at room temperature under magnetic stirring for 4 h. The precipitate formed was filtered off, washed with isopropyl alcohol, and dried in a desiccator. We stirred (B) 0.002 mol (0.41 g) of 2-imino-2H-chromene-3-carbonitrile and 0.003 mol (0.54 g) of 3-nitrobenzhydrazide into THF at room temperature under magnetic stirring for 4 h. The precipitate formed is filtered off, washed with isopropyl alcohol, and dried in a desiccator. The product is recrystallized from isopropyl alcohol.

M.p. = 275–278 °C. Light brown crystals. Calculated, %: C, 58.12; H, 3.73; N, 19.93; O, 18.22. C₁₇H₁₃N₅O₄. Found, %: C 58.19; H 3.75; N 20.02. IR, ν, cm⁻¹: 3421, 3255 (NH); 3065 (Ar-H); 2961, 2870 (Csp3-H); 1133 (C-O-C). ¹H NMR (Acetone-d6), δ, ppm: 4.79–4.82 (H¹, d, 1H. J = 8.7 Hz); 5,84 (H², dd, 1H. J = 9 Hz); 6.38 (ArH⁵, d, 1H. J = 3.7 Hz); 7.19–7.28 (ArH⁶, m, 1H); 7.33–7.41 (ArH⁷, m, 1H); 7.64 (ArH¹¹, s, 1H); 7.76–7.78 (ArH⁸, d, 1H. J = 8.5 Hz); 7.80 (=NH, s, 1H); 7.85 (=NH, s, 1H); 8.02 (ArH¹⁴, t, 1H. J = 7.6 Hz); 8.07 (ArH¹⁵, d, 1H. J = 8.4 Hz); 8.29 (ArH¹³, d, 1H. J = 8.4 Hz); 10.99 (NH, s, 1H). ¹³C NMR (DMSO-d6), Cδ, ppm: 53,71 (C²); 51,85 (C¹); 110,3 (C⁵); 116.61 (C⁷); 122.02 (C¹⁴); 122,43 (C¹¹); 123.88 (C¹³); 129.18 (C¹⁵); 129.64 (C⁶); 131.42 (C⁸); 144.79 (C¹⁰); 163.35 (C¹⁶); 187.42 (C³). ¹H/¹³C HSQC (Acetone-d6), δ, ppm: 4.8/51,85 (H¹/C¹); 5,84/53,71 (H²/C²); 6,38/110,3 (H⁵/C⁵); 7.23/129.64 (H⁶/C⁶); 7.37/116.61 (H⁷/C⁷); 7,64/122,43 (H¹¹/C¹¹); 7.78/131.42 (H⁸/C⁸); 8.01/122.02 (H¹⁴/C¹⁴); 8.07/129.18 (H¹⁵/C¹⁵); 8.29/123.88 (H¹³/C¹³). ¹H/¹³C HMBC (Acetone-d6), δ, ppm: 4.81/53.70 (H¹/C²); 4.8/144.79 (H¹/C¹⁰); 4.8/163.35 (H¹/C¹⁶); 4.8/187.42 (H¹/C³); 5.84/51.85 (H²/C¹); 5.84/187.42 (H²/C³). Yield: 60% (A), 63% (B).

• 13,13a-dihydrobenzo[b]chromeno[4,3-e][1,4]diazepine-6,7-diamine 3

(A) Equimolar amounts of 2-imino-2H-chromene-3-carbonitrile 0.002 mol (0.41 g,) and orthophenylenediamine 0.002 mol (0.22 g) were stirred into an ultrasonic bath in isopropyl alcohol at 50 °C for 4 h. The precipitate formed is filtered off, washed with hexane, and dried in desiccators. The product is recrystallized from isopropyl alcohol.

M.p. = 289–291 °C. The beige crystals. Calculated, %: C, 69.05; H, 5.07; N, 20.13; O, 5.75. C₁₆H₁₄N₄O. Found, %: C 69.30; H 5.10; N 20.27. ¹H NMR (DMSO-d6), δ, ppm: 6.30 (NH, s, 1H), 6.50 (H¹, s, 1H), 7.14 (-NH₂, s, 2H), 7.20 (-NH₂, s, 2H), 7.49–7.57 (ArH, m, 6H,), 7.78 (ArH, t, 1H. J = 7.9 Hz,), 8.94 (ArH, d, 1H. J = 8.5 Hz,). ¹³C NMR (DMSO-d6), Cδ, ppm: 50.68 (C¹); 108.94 (C^1a); 118.90 (C Ar); 125.38 (C Ar); 125.92 (C Ar); 134.90 (C Ar); 142.58 (C^3a); 152.26 (C-NH₂); 152.64 (C-NH₂). ¹H/¹³C HSQC (DMSO-d6), δ, ppm: 6.49/50.68 (H¹/C¹). ¹H/¹³C HMBC (Acetone-d6), δ, ppm: 6.29/142.58 (NH/C^3a). Yield: 74% (A).

4. Conclusions

Thus, the novel chromeno[4,3-c]pyrazoles 1,2 and chromeno[4,3-e][1,4]diazepine 3 were synthesized. Compounds 1b, 3 were synthesized using a «green chemistry» approach under ultrasonic activation. The influence of reaction parameters, such as temperature, solvent type, and activation type, was studied.

Three-component reactions of malononitrile, salicylic aldehyde, and hydrazides under heating mainly led to the formation of the Schiff base, but three-component and step-wise reactions of malononitrile, salicylic aldehyde, and 3-nitrobenzhydrazides in THF led to the new chromeno[4,3-c]pyrazole 2. Thus, the reaction conditions significantly affect the direction and depth of the reaction of malononitrile, salicylic aldehyde, and hydrazides.