Synthesis of benzofuro[3,2-b]furo[2,3-d]pyridin-4(5H)-ones, derivatives of a novel heterocyclic system

Introduction

Benzofuro[3,2-b]pyridines are biomedically attractive compounds. For instance, some 2-oxo-3-carboxylic acids derived from them act as endothelin receptor antagonists [1], [2], and the esters are Р₂Х₄ receptor modulators [3]. A number of analogous heterocyclic systems with the benzo[d]-annelated pyridine ring, such as benzofuro[3,2-c]isoquinolines [4], [5], [6], inhibit hepatitis C viral infection [7] and are used to treat erectile dysfunction [8], inflammation and cardiovascular diseases [9]. At the same time, heteroannelated benzofuropyridines are much less studied and the reported compounds are restricted to a few quinolino [10], [11] and coumarino derivatives [12], [13] with anti-inflammatory and antimicrobial activities. Their analogues with a fused furan ring are hitherto unknown. These structures can be regarded as polycyclic systems originated from superposition of benzofuro[3,2-b]pyridine and furo[3,2-c]pyridine moieties. It is worth noting, that among furo[3,2-c]pyridine derivatives used for reversible control of protein transport [14], melanin-concentrating hormone receptor 1 antagonists [15] and protein kinase inhibitors [16] have been found.

Most of the benzo and heteroannelated benzofuropyridines described in the literature have been synthesized starting with salicylonitriles [4], [5], [6], [11], [12], [13] under the conditions of the Pictet-Spengler reaction. One approach used in this paper, provides a convenient way to obtain benzofuro[3,2-b]furo[2,3-d]pyridine, a novel heterocyclic system. More specifically, easily accessible methyl 2-(chloromethyl)-3-furoate [17] has been used as a bis-electrophilic component in the condensation with a salicylonitrile.

Results and discussion

Methyl 2-(chloromethyl)-3-furoate (1) is an effective reagent for the alkylation of salicylonitriles 2a–i. The reaction conducted in the presence of K₂CO₃ in DMF solution at 60°C produces methyl 2-[(cyanophenoxy)methyl]-3-furoates 3a–i in 69–80% yields (Scheme 1). When heated with t-BuOK in DMF solution at 65°C, compounds 3a–i are converted in 67–83% yields to derivatives 5а–h of benzofuro[3,2-b]furo[2,3-d]pyridine, a hitherto unknown heterocyclic system (Scheme 1). This reaction is a variation of tandem cyclization, with its first step proceeding by the Thorpe-Ziegler scheme and leading to intermediate aminobenzofurans 4 that undergo intramolecular condensation between the amino and methoxycarbonyl groups to form the pyridone ring.

Scheme 1

For compound 3i containing a fluorine atom at position 3 of the benzene ring, it was found using liquid chromatography-mass spectrometry (LC-MS) analysis that the reaction mixture after 3 h at 65°C contained not only 54% of 6-fluorinated product 5i but also 40% of 6-methoxy derivative 5j. Heating of 3i at 90°C led to the formation of the product 5j exclusively, which was isolated in 68% yield. This transformation is caused by a nucleophilic substitution of compound 5i with MeOK which is generated under the reaction conditions as a side product of the cyclocondensation (Scheme 2).

Scheme 2

The possibility of the synthesis of compound 5a without isolation of the intermediate product 3a was studied using salicylonitrile 2a. It was found that the addition of t-BuOK after the first step and heating of the reaction mixture at 65°C also leads to the formation of 5a, albeit in a low yield of 24%.

Structural determination of the synthesized compounds was performed using analytical and spectral methods. In particular, the infrared (IR) spectra of compounds 5а–j feature characteristic N-H (ν_max 3154–5170 cm⁻¹) and C=O (ν_max 1665–1671 cm⁻¹) absorption peaks. Typical downfield signals of the C=O carbon of the pyridone moiety (δ 158–164) are observed in carbon-13 nuclear magnetic resonance ( ¹³C NMR) spectra.

Conclusion

An efficient construction of the previously unknown benzofuro[3,2-b]furo[2,3-d]pyridine system based on tandem heterocyclization of 2-[(2-cyanophenoxy) methyl]- 3-furoates was developed. The products, due to the presence of a lactam fragment can be considered as promising scaffolds for further modifications aiming at the identification of bioactive derivatives.

Experimental

All commercially available chemicals were purchased from Sigma-Aldrich Chemicals (Steinheim, Germany). Methyl 2-(chloromethyl)-3-furoate 1 and salicylic nitriles 2a–i were purchased from Enamine Ltd (Kyiv, Ukraine). The reactions were monitored by thin-layer chromatography (TLC) using commercial silica gel plates Silufol UV-254. Melting points were taken on a hot-stage apparatus. IR spectra were obtained on a Bruker Vertex 70 spectrometer in KBr pellets. Proton nuclear magnetic resonance (¹H NMR) (400 MHz) and ¹³C NMR (100 MHz) spectra were recorded on a Varian VXR-400 spectrometer using deuterated dimethyl sulfoxide-d₆ (DMSO-d₆) as a solvent. Elemental analyses were conducted at the Laboratory of Organic Analysis, Institute of Organic Chemistry, National Academy of Science of Ukraine. Electrospray ionization mass spectra (ESI-MS) were recorded on an Agilent 1100/DAD/HSD/VLG119562 instrument.