Novel approach for the synthesis of 2-arylfuro[3,2-b]pyran-3-carbaldehydes based on acid-catalyzed cyclization of allomaltol containing enaminones

Abstract The novel and efficient approach for the synthesis of various 2-arylsubstituted furo[3,2-b]pyran-3-carbaldehydes was developed. The studied method is based on acid-catalyzed cyclization of enaminones bearing allomaltol fragment. The distinctive feature of the suggested protocol is the other direction of heterocyclization of starting enaminoketones in contrast to the previously described approach leading to 3-aroylfuro[3,2-b]pyranes. The advantages of this synthesis are easily accessible starting compounds, mild reaction conditions, and simple workup procedure avoiding chromatographic purification. The synthetic utility of obtained aldehydes was demonstrated by the preparation of various derivatives. The structure of one furo[3,2-b]pyran-3-carbaldehyde was proved by X-ray diffraction. Graphical Abstract


Introduction
2-Arylfurans are an important class of heterocyclic compounds that are widely used in various fields of science. Different biological activity of products of this class is of considerable interest. Several examples include a family of 2-arylfurans that were tested as potential anticancer and antimicrobial drugs. [1][2][3][4] It was demonstrated that some molecules with a 2-arylfurans core displayed significant antiplasmodial activity. [5] Also, the studied products can be considered as a preferable class of multipotent Alzheimer's disease modifying agents. [6][7][8] Finally, compounds containing the 2-arylfuran unit were employed as HIV-1 fusion inhibitors, [9,10] antioxidant agents, [11] and for treatment of tropical parasitic diseases. [12] Another direction of application of 2-arylfurans is associated with their interesting photochemical properties. Thus, it was shown that various 1,3,5-hextariene systems, bearing a 2-arylfuran fragment, undergo 6p-electrocyclization under UV-irradiation. In this case, polycyclic products containing benzofuran core are formed as a result of the reaction. [13][14][15][16] Thus, the scope of employment of 2-arylfuran derivatives extends over a wide range from medicinal chemistry to molecular photonics.
Preparative methods for the synthesis of 2-arylfurans are quite diverse. At the same time, the available literature data can be divided into two main types of processes. The first approach is based on the introduction of an aryl residue into the starting compound containing a furan fragment. In this case, considerable attention is paid to methods that include the use of transition metal-catalyzed coupling reactions. [17][18][19][20][21] Another way to construct the studied systems is based on the formation of furan ring as a result of heterocyclization reactions. [22][23][24][25][26] Among the latter type of processes approaches including the use of the methodology of multicomponent reactions are of considerable interest. [13][14][15][16][27][28][29][30] Wherein, special attention is drawn to synthetic methods that allow obtaining functional derivatives of 2-arylfurans. The application of such objects as starting compounds opens up access to a wide range of products containing 2-arylfuran moiety. Therefore, the development of novel synthetic methods for the direct preparation of functionally substituted compounds of this class from readily accessible materials is very important.
Continuing our research in the field of chemistry of various furan containing products, for the first time herein, we elaborate a highly efficient approach for the synthesis of 2-arylfuro[3,2-b]pyran-3-carbaldehydes 3 based on acid-catalyzed cyclization of enaminones 1 containing allomaltol moiety (Scheme 1B). Note that we previously studied the intramolecular cyclization of starting compounds 1 in acetic acid leading to 3-aroylfuro[3,2-b]pyranes 2 in good yields (Scheme 1A). [31] In this case, heterocyclization proceeds with the participation of the hydroxyl group of the allomaltol fragment Scheme 1. Acid-catalyzed cyclization of enaminones 2. and the enamine moiety, while the carbonyl unit is remained unchanged. At the same time, many similar examples are known in the literature concerning cyclization of hydroxyl function at the aroyl fragment resulting in the formation of various 2-arylfurans. [13][14][15][16]22,[27][28][29][30][31][32][33][34] As a rule, such processes require the employment of strong acids, for example, HCl or p-TsOH. It could be assumed that varying the type of used acid would allow one to change the direction of heterocyclization and obtain the corresponding 2-arylfuran derivatives.

Results and discussion
Starting enaminone 1a was chosen as a model object for studying the above hypothesis. We tested the cyclization of compound 3a using strong acids under various conditions and the results are presented in Table 1.
Initially, we selected a mixture of hydrochloric and acetic acids, which was previously used for a similar type of cyclization ( Table 1, Entry 1-4). In this case, we were able to obtain product 3a in a low yield, wherein carrying out the reaction at room temperature is more preferable ( Table 1, Entries 1 and 2). At the same time, prolonged heating in this medium led to decomposition of the target product 3a (Table 1, Entry 4). Replacing hydrochloric acid with other strong acids and use of acetic acid as a solvent did not allow obtaining compound 3a (Table 1, Entries 5-8). The application of p-TsOH in other organic solvents also led to negative results (Table 1, Entries 9 and 10). Apparently, this is due to the fact that the presence of water in the reaction mixture is necessary for the formation of product 3a. Therefore, we further tested the studied  [11][12][13][14][15]. It was shown that in all these cases, product 3a is formed, while the optimal conditions are the use of concentrated hydrochloric acid at room temperature for 16 h (Table 1, Entry 11). Note that an increase in the process time did not affect the yield of the target 2-arylfuran 3a (Table  1, Entry 12). At the same time, refluxing in concentrated hydrochloric acid led to a significant decrease in the yield of the product 3a (Table 1, Entry 13). We also emphasize that other strong acids are less effective under these conditions (Table 1, Entries 14  and 15).
Thus, the optimal conditions were developed for the studied cyclization, allowing the preparation of various 2-arylfuro[3,2-b]pyran-3-carbaldehydes 3 in good yields ( Table  2). It should be mentioned that the suggested method is of a general nature and makes it possible to utilize the starting enaminoketones 1 containing both donor and acceptor aryl substituents. Note that the presented method is the first example of the synthesis of furo[3,2-b]pyran-3-carbaldehydes.
The structure of product 3b (Fig. 1) has been determined by X-ray diffraction (see Supplemental Material, Tables S1-S6).
The plausible mechanism for the formation of 2-arylfuro[3,2-b]pyran-3-carbaldehydes 3 and an alternative route leading to 3-aroylfuro[3,2-b]pyranes 2 are shown in Scheme 2. Thus, intramolecular cyclization of the starting compound 1 into product 2 occurs in refluxing acetic acid (Pathway A). Initially, Michael addition involving the hydroxyl group of the allomaltol fragment and the double bond of the enaminoketone moiety  Probably, aforementioned reaction is not acid-catalyzed process and acetic acid acts only as a high-boiling solvent, which also binds releasing dimethylamine. Note that addition of nucleophilic agents by the Michael reaction, followed by the elimination of the amine are typical for similar enaminoketones. [35][36][37][38][39] It is important to emphasize that the presence of a strong acid drastically changes direction of the reaction (Pathway B). In this case, apparently, protonation of the oxygen atom of the enaminoketone fragment occurs initially with the formation of the cation C, which is stabilized by conjugation with the dimethylamine group. Further addition of the hydroxyl group of the allomaltol fragment at the carbonyl fragment leads to the intermediate D. Next, elimination of water leads to the aromatization of furan ring and formation of the iminium salt E. Finally, hydrolysis of salt E occurs resulting in formation of the target product 1 accompanied by the liberation of dimethylamine hydrochloride. Thus, the presented scheme demonstrates the difference between thermal cyclization leading to 3-aroylfuro[3,2-b]pyranes 2 and an acid-catalyzed process, which allows obtaining the corresponding 2-arylfuro[3,2b]pyran-3-carbaldehydes 3.
The synthetic utility of the obtained 2-arylfurans 3 was demonstrated by its further derivatization (Scheme 3). The presented compounds 3 were characterized by various reactions of the aldehyde moiety. Thus, interaction of 2-arylfuran 3a with hydrazines 4 led to corresponding hydrazones 5. At the same time reaction with C-nucleophiles, such as malononitrile 6 and Meldrum's acid 7 allows one to obtain hetarylmethylene derivatives 8 and 9.

Conclusion
In summary, we developed convenient method for the preparation of diverse 2-arylsubstituted furo [3,2-b]pyran derivatives bearing aldehyde function. The presented approach includes acid-catalyzed heterocyclization of enaminoketones containing allomaltol fragment. The distinctive feature of the considered method is another pathway of process in contrast to the previously described protocol resulting in formation of 3-aroylfuro[3,2b]pyranes. The advantages of studied approach are readily available starting materials, mild reaction conditions, and simple workup procedure, which can avoid chromatographic purification. The synthetic utility of prepared aldehydes was exemplified by the condensation with various nucleophile reagents. The structure of one of the target products was confirmed by X-ray diffraction.

Experimental
Unless otherwise stated, all starting chemicals were commercially available and were used as received. Compounds 1 and 13 were prepared according to a procedure described in the literature. [31,40] NMR spectra were recorded with Bruker AM 300 (300 MHz), Bruker DRX 500 (500 MHz), and Bruker AV 600 (600 MHz) spectrometers in DMSO-d 6 . Chemical shifts (ppm) are given relative to solvent signals [DMSO-d 6 : 2.50 ppm ( 1 H NMR) and 39.52 ppm ( 13 C NMR)]. High-resolution mass spectra (HRMS) were obtained on a Bruker micrOTOF II instrument using electrospray ionization (ESI). The melting points were determined on a Kofler hot stage. IR spectra were recorded on a Bruker ALPHA spectrophotometer in a KBr pellet.
General procedure for the synthesis of 2-arylfuro[3,2-b]pyran-3-carbaldehydes 3 A mixture of enaminone 1 (1 mmol) and HCl conc (10 ml) was kept at room temperature for 16 h. Then H 2 O (100 ml) was added, and the obtained mixture was stirred for 0.5 h. The resulting precipitate was filtered off and washed with a saturated solution of sodium bicarbonate (3 Â 10 ml) and H 2 O (3 Â 10 ml).
Full experimental details, copies of 1 H, 13 C and 19 F NMR spectra can be found via the 'Supplemental material' section of this article's webpage.