A. V. Trifonov

Pyridoxal-derived Schiff’s bases

Over the past few decades synthesis of functionalized derivatives of pyridoxal (vitamin B6) and study of their biological activity have received a great deal of interest [1–3]. Among these compounds, monoand bis-azomethines of pyridoxal occupy an important place [4–6]. In practice, pyridoxal hydrochloride is often used since free pyridoxal is unstable and undergoes irreversible fast transformation.

Synthesis of aminofuropyridines via the reaction of aminosilanes with pyridoxal

We studied a possibility of modifying pyridoxal using aminosilanes and silazanes. The reactions of aliphatic and aromatic aldehydes with aminosilanes and silylamides of carboxylic acids occurred via attachment of the carbonyl reagent at the Si–N bond to form the corresponding trimethylsiloxy derivatives. In these reactions zinc chloride, lithium perchlorate, ptoluenesulfonic acid, and trimethylsilyl triflate were used as catalysts [4–9]. Depending on the reaction conditions, the interaction of aminosilanes with α,βunsaturated aldehydes resulted in 1,3-bis(dialkylamino)alkenes or the corresponding aminals [10, 11].

Phosphorus-containing salts derived from pyridoxal

Pyridoxal in the form of pyridoxal 5′-phosphate (vitamin B6) plays an important role in biochemical processes from protozoa to humans [1–3]. Pyridoxal is a cofactor for decarboxylation [4], amino acid racemization [5–7], transamination of α-keto acids, etc. [8–10]. Since the discovery of vitamin B6, the structure of pyridoxal has long remained not clearly understood. It reacts as aldehyde with primary amines to give Schiff bases, whereas its H NMR spectra in different solvents indicate its hemiacetal structure. For example, it was shown in [11, 12] that pyridoxal hydrochloride in alcoholic solution is converted into the corresponding monoalkyl acetal. In this communication we report on the reaction of “free” pyridoxal with phosphorous acid in alcoholic medium. We have found no published data on the formation of salt structures by pyridine or its derivatives with phosphorous acid. The reactions of equimolar amounts of pyridoxal (1) and phosphorous acid in alkanols led to the formation of crystalline compounds 2a–2e with sharp melting points. The structure of 2a–2e was determined on the basis of IR, H and P NMR, and MALDI mass spectra, elemental analyses, and X-ray diffraction data. The P NMR spectra of 2a–2e contained a signal at δP 0.90–2.50 ppm (JPH = 627–631 Hz), unambiguously indicating the presence of a phosphonate moiety. According to the H NMR spectra, molecules of 2a–2e contained an alkoxy group of the corresponding alcohol. Methylene protons of the former 5-CH2 group resonated as two doublets with a coupling constant of 13.1–13.3 Hz, and the acetal proton appeared as a singlet. The signal from the CH proton neighboring to the pyridine nitrogen atom was slightly displaced downfield, but the downfield shift was smaller than that observed in going from pyridoxal to pyridoxal hydrochloride. The OH proton in all compounds 2a–2e gave rise to a broadened singlet. The IR spectra of 2a– 2e displayed a series of absorption bands in the region 1800–2500 cm, which are typical of N–H group. These findings allowed us to presume that the products are furopyridine derivatives possessing an iminium nitrogen atom; this is indirectly supported by the good solubility of 2a–2e in water. According to the X-ray diffraction data, compounds 2a and 2b crystallize in monoclinic (P21/n) and triclinic (P-1) crystal systems, respectively. The independent part of a unit cell contains two independent furopyridinium cations and two H2PO3 counterions. The five-membered heterocycles in both molecules have O-envelope conformation. The alkoxy group occupies the axial position. Analysis of intermolecular interactions revealed formation of

1-Alkoxy-7-hydroxy-1,3-dihydrofuro[3,4- c ]pyridinium Salts

New salt structures have been synthesized from pyridoxal and various organic and inorganic acids.

Azomethines Based on Pyridoxal-Derived Aromatic Aldehydes

The reaction of pyridoxal with 2,4-dihydroxybenzaldehyde in a hydrochloric acid solution gave 1-(5-formyl-2,4-dihydroxyphenyl)-7-hydroxy-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-5-ium chloride. Treatment of the latter with sodium hydride in ethanol afforded a free aldehyde in 85% yield. A series of azomethines and imidazolidines was obtained by reacting the obtained aldehyde with various amines and diamines.

Reactions of pyridoxal with aromatic carboxylic acids in alcoholic medium

Reactions of pyridoxal with benzoic acid and its derivatives in alcoholic medium afforded alkoxyfuropyridinium salts with potential biological activity.

Reaction of pyridoxal imine with phosphonic acid derivatives

Pyridoxal is one of the three natural forms of vitamin B6. Its biologically active form, pyridoxal 5-phosphate, plays an important role in biochemical processes by catalyzing various reactions, including amino acid metabolism. The action of pyridoxal as cofactor in most enzymatic reactions involves initial formation of Schiff bases with substrates. Up to now, a large number of functionalized derivatives of pyridoxal have been synthesized, including Schiff bases possessing biological activity [1–7]. Reactions of PH-containing compounds with Schiff bases derived from pyridoxal have not been reported. It is known that aminophosphonic acid derivatives exhibit a broad spectrum of biological activity [8]. One of the simplest and most convenient methods for their preparation is addition of dialkyl phosphonates to Schiff bases (Pudovik reaction). It ensures mild conditions and high yields of the target products [9]. We have found that the addition of diethyl phosphonate to Schiff base 1 in the presence of sodium ethoxide leads to the formation of crystalline compound 4 (Scheme 1). According to the H NMR and mass spectral data, molecule 4 contains only one ethyl group. The X-ray analysis of a single crystal of 4 showed that the product is an inner salt with proton localized on the pyridine nitrogen atom. Compound 4 crystallized in Pbca space group belonging to orthorhombic crystal system. All atoms in 4 occupy general positions. The phosphorus atom has a tetrahedral bond configuration, and the chiral carbon atom has R configuration. The ethoxy group is disordered by two positions with a population ratio of 60 : 40. The C–P bond is almost orthogonal to the benzene ring plane (see figure).

Reaction of pyridoxal and its azomethines with hydrophosphoryl compounds

GRAPHICAL ABSTRACT ABSTRACT The products of carbonyl phosphonylation of pyridoxal with alkylphosphinic acid ethyl esters, phosphorous acid dialkyl esters have been obtained for the first time. In some cases, the products of addition are hydrolytically unstable and stabilize by forming internal betaine structures. The reaction of pyridoxal with phosphorous acid in alcohol solutions gives alkoxyfuropyridines possessing the iminium nitrogen atom.

Phosphorus containing azomethines and furopyridines on the basis of pyridoxal

GRAPHICAL ABSTRACT ABSTRACT New O-phosphorylated pyridoxal derivatives, based on the azomethine reaction with acid chlorides P(IV) were synthesized. Depending on the nature of the substituent on the nitrogen atom final products are phosphorylated furopyridines or azomethines of pyridoxal.