Ammonium Salts of 5-(3-Chromenyl)-5 H -chromeno[2,3- b ]pyridines

: The ammonium salts of many drugs have signiﬁcantly improved the solubility and, accordingly, the bioavailability of medicinal substances in the human body. 5-(4-Hydroxy-2-oxo-2 H -chromen-3-yl)-5 H -chromeno[2,3- b ]pyridines are potential NPY1R ligands, which are attractive for antiobesity treatment. Ammonium salts of 5 H -chromeno[2,3- b ]pyridines were previously unknown. In this communication, it was found that the four-component reaction of salicylaldehyde, 2-aminoprop-1-ene-1,1,3-tricarbonitrile, 4-Hydroxy-2 H -chromen-2-one and amines results in the formation of ammonium salts of 5-(3-chromenyl)-5 H -chromeno[2,3- b ]pyridines. The structure of these previously unknown compounds was conﬁrmed by means of 1 H, 13 C NMR and IR spectroscopy, mass spectrometry and elemental analysis.


Introduction
Solubility is one of the most important parameters to achieve the desired concentration of a drug in the systemic circulation for coveted pharmacological response [1]. Control of the solubilization characteristics of drugs is one of the main directions in the development of modern drug delivery systems. Methods for increasing the solubility and bioavailability of active pharmaceutical ingredients are being actively developed.
Solubility plays a significant role in the action of drugs, especially those intended for oral administration. In this regard, about 40% of manufactured drug substances are classified as practically insoluble, and about 85% of the best-selling drugs in the USA and Europe are taken orally; research in this area is very relevant [2]. One of the methods for improving solubility is the chemical modification of the drug substance [3]. An example of such a modification is the formation of salts.
Thus, the synthesis of highly bioavailable chromeno [2,3-b]pyridines is an important challenge for researchers.
Herein, we report the four-component synthesis of the previously unknown ammonium salts of 5-(3-chromenyl)-5H-chromeno [2,3-b]pyridines and present a study of their structure and chemical properties.

Multicomponent Synthesis of Ammonium Salts of 5-(3-Chromenyl)-5H-chromeno[2,3-b] pyridines 5
Multicomponent reactions represent a powerful tool in the arsenal of organic synthesis; its synergistic utilization with other green chemistry principles would bring organic chemists one step closer to the ideal synthesis [10].

Multicomponent Synthesis of Ammonium Salts of 5-(3-Chromenyl)-5H-chromeno[2,3-b]pyridines 5
Multicomponent reactions represent a powerful tool in the arsenal of organic synthesis; its synergistic utilization with other green chemistry principles would bring organic chemists one step closer to the ideal synthesis [10].

Multicomponent Synthesis of Ammonium Salts of 5-(3-Chromenyl)-5H-chromeno[2,3-b]pyridines 5
Multicomponent reactions represent a powerful tool in the arsenal of organic synthesis; its synergistic utilization with other green chemistry principles would bring organic chemists one step closer to the ideal synthesis [10].
Now, we wish to report our results on the efficient four-component transformation of salicylaldehyde 1, 2-aminoprop-1-ene-1,1,3-tricarbonitrile 2, 4-Hydroxy-2H-chromen-2-one 3 and amines 4 into the previously unknown ammonium salts of 5-(3-chromenyl)-5H-chromeno[2,3-b]pyridines 5 in EtOH at 78 °C, as shown in Scheme 2. The amine in this reaction is both a reagent and a catalyst. Compounds 5a-d were synthesized in 77-81% yields ( Table 1). The reaction process is environmentally friendly because no amine catalyst becomes waste when reacted. Ethanol is an environmentally preferable solvent conforming to green chemistry. It is available from renewable sources, such as by the fermentation of starch.

Scheme 2. Synthesis of ammonium salts of 5-(3-chromenyl)-5H-chromeno[2,3-b]pyridines 5.
Compounds 5a-d were synthesized in 77-81% yields ( Table 1). The reaction process is environmentally friendly because no amine catalyst becomes waste when reacted. Ethanol is an environmentally preferable solvent conforming to green chemistry. It is available from renewable sources, such as by the fermentation of starch.
The first stage was a rapid Knoevenagel condensation of salicylaldehyde 1 and malononitrile dimer 2, and then the formation of intermediate 6 with the expulsion of a hydroxide anion [13]. This hydroxide anion instantly catalyzed a rapid cyclization of intermediate 6 into intermediate 7. Then, subsequent Michael addition and cyclization formed the chromeno[2,3-b]pyridine 8. In conclusion, the acid-base interaction of compound 8 and the corresponding amine 4 led to the formation of ammonium salt 5.  Taking into consideration the results of the 1 H NMR monitoring of the Pot, Atom and Step Economy (PASE) reaction of salicylaldehydes, malononitrile dimer and hydroxyquinolinone [12], the following mechanism for the four-component reaction of salicylaldehyde 1, 2-aminoprop-1-ene-1,1,3-tricarbonitrile 2, 4-Hydroxy-2H-chromen-2-one 3 and amines 4a-d was proposed, as shown in Scheme 3.  Taking into consideration the results of the 1 H NMR monitoring of the Pot, Atom and Step Economy (PASE) reaction of salicylaldehydes, malononitrile dimer and hydroxyquinolinone [12], the following mechanism for the four-component reaction of salicylaldehyde 1, 2-aminoprop-1-ene-1,1,3-tricarbonitrile 2, 4-Hydroxy-2H-chromen-2-one 3 and amines 4a-d was proposed, as shown in Scheme 3.  5-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-5H-chromeno[2,3-b]pyridines 8 are known as potential neuropeptide Y1 receptor (NPY1R) ligands, which are attractive for antiobesity treatment [11]. NPY1Rs are the most abundant in the hypothalamus; this part of the human brain is known to control eating behavior [14]. Thus, we synthesized a supposedly more soluble and more bioavailable form of the ligand for the NPY1R.

NMR Spectroscopy Study of Morpholin-4-ium 3-(2,4-Diamino-3-cyano-5H-chromeno[2,3-b]pyridin-5-yl)-2-oxo-2H-chromen-4-olate 5d
The 1 H NMR spectrum of compound 8 (Figure 1, bottom spectrum) showed a very broad signal from the proton of the OH-group at 12.3 ppm due to exchange with water and, probably, tautomerism. For the same reason, protons in the immediate neighborhood of the hydroxyl group (H 5 , H 5 ') produced broadened signals in the spectrum. Protons of amino groups also produced wide signals.  For the ammonium salt 5d, the protons of the NH 2 -group at the second position produced a narrow singlet at 6.04 ppm (Figure 1, top spectrum). The signal from 4-NH 2 group remained broad and shifted slightly to the downfield. The signal from H 5 appeared as a sharp singlet, and H 5 ' turned into a clear doublet at 7.89 ppm and a constant J equal to 6.3 Hz. The morpholinium cation showed a change in the chemical shifts of the nuclei of hydrogen atoms in comparison with the signals from morpholine in the form of a free base [15]. The signal of CH 2 -fragments of positions 3 and 5 was shifted by ∆δ = 0.45 ppm, and the signal for protons 2 and 6 was shifted by ∆δ = 0.16 ppm to the downfield. NH 2 + protons produced a signal at 8.61 ppm, which is typical for aliphatic ammonium salts.
The yields of compound 8 are practically quantitative and do not depend on the structure of salt 5. Scheme 4. Acidification of ammonium salts 5.
All melting points were measured with Gallenkamp melting-point apparatus (London, UK) and were uncorrected. 1 H and 13 C NMR spectra were recorded in DMSO-d6 with Bruker AM300, Bruker AV500 and Bruker AV600 spectrometers (Billerica, MA, USA) at ambient temperature. Some OH, NH, NH2 and NH2 + signals were exchanged with D2O (it is present as an impurity in DMSO-d6). Chemical shift values are relative to Me4Si. The IR spectrum was recorded with a Bruker ALPHA-T FT-IR spectrometer (Billerica, MA, USA) in KBr pellet. The MS spectrum (EI = 70 eV) was obtained directly with a Kratos MS-30 spectrometer (Manchester, UK). For elemental analysis, a 2400 Elemental Analyzer (Perkin Elmer Inc., Waltham, MA, USA) was used.
The yields of compound 8 are practically quantitative and do not depend on the structure of salt 5.
All melting points were measured with Gallenkamp melting-point apparatus (London, UK) and were uncorrected. 1 H and 13 C NMR spectra were recorded in DMSO-d 6 with Bruker AM300, Bruker AV500 and Bruker AV600 spectrometers (Billerica, MA, USA) at ambient temperature. Some OH, NH, NH 2 and NH 2 + signals were exchanged with D 2 O (it is present as an impurity in DMSO-d 6 ). Chemical shift values are relative to Me 4 Si. The IR spectrum was recorded with a Bruker ALPHA-T FT-IR spectrometer (Billerica, MA, USA) in KBr pellet. The MS spectrum (EI = 70 eV) was obtained directly with a Kratos MS-30 spectrometer (Manchester, UK). For elemental analysis, a 2400 Elemental Analyzer (Perkin Elmer Inc., Waltham, MA, USA) was used. A solution of salicylaldehyde 1 (0.122 g, 1 mmol), 2-aminoprop-1-ene-1,1,3-tricarbonitrile 2 (0.132 g, 1 mmol), 4-Hydroxy-2H-chromen-2-one 3 (0.162 g, 1 mmol) and the corresponding amine 4 (1 mmol) in ethanol (4 mL) was refluxed in a round-bottom flask for 1 h. After the reaction was finished, the reaction mixture was chilled to 0 • C to crystallize the solid compound 5, which was then filtered out, twice rinsed with ice-cold ethanol (2 × 2 mL) and dried under reduced pressure.