1. Introduction

Furan derivatives are valuable structural motifs as an important class of five-membered containing oxygen heterocycles in both naturally occurring and artificial compounds with their diverse and potent biological properties [1-5]. Substituted furans also play an important role in synthetic organic chemistry due to their great potential in material science [6, 7] and their usefulness as building blocks [8-10]. In general, substituted furans were synthesized by the two classical and well-established methods including Feist- Bénary cyclocondensation of 1, 3-dicarbonyl compounds with haloketones and Paal-Knorr cyclocondensation of 1, 4-dicarbonyl compounds [11, 12]. Recently, due to their widespread applications in synthetic pharmaceuticals, agrochemicals, and material science, the development of efficient methods for the preparation of polysubstituted furans has attracted substantial interest from medicinal and synthetic chemists [13-19]. Among them, important protocols involved the transition-metal-catalyzed annulations of allenyl, alkynyl, or cyclopropyl ketones or other derivatives [20-24]. In addition to the conventional annulation synthesis, the functionalization of existing furans was another prominent reaction, such as Pd catalyzed direct arylation of furans via C-H activation [25]. Additionally, a simple ring opening reaction or/and cycloisomerization reaction of donor-acceptor cyclopropanes also has provided powerful means of access to diversely substituted furans [26-31]. Although many traditional methods have proven very effective for the synthesis of substituted furans, efficient approaches for the synthesis of polysubstituted furans with flexible substituent patterns from simple and readily available precursors are of great value.

In recent years, D-A cyclopropanes have drawn considerable attention due to the simplicity of their synthesis and potential for variation of the aryl groups, which easily undergo a variety of ringopening reactions under the influence of a variety of conditions [32-36]. A geminal substitution of the donor and acceptor of cyclopropanes induces a high polarization of the C-C bond via the push-pull effect, which can easily be cleaved heterolytically, cyclopropanes are readily transformed into useful 1, 3-dipoles via a ring-opening reaction by treatment with Lewis acids or bases for a multitude of different reactions [37, 38]. As new type of threecarbon synthons, 2-aroyl-3-aryl-1-cyanocyclopropane-1-carboxylates with one donor (aryl) and three acceptor (aroyl, cyano and carboxylate) substituents in the vicinal positions have been used in the construction of aromatic rings. Because of the high polarization of two of three C-C bonds of the ring, the cyclopropanes may be transformed into two 1, 3-dipoles via a ring-opening reaction for the diversity of reactions. Previously, we have reported the opening ring of 1-cyanocyclopropane-1-carboxylates promoted by common organic bases such as piperidine, triethylamine, and DBU [31, 36, 39-41]. Especially, the C-C bond (path a, Scheme 1) of the cyclopropane was cleaved even more easily promoted by combinational iodine/trimethylamine, the ring-opening/cyclization domino reaction of 1-cyanocyclopropane-1-carboxylates formed straightforwardly fully substituted 2-aminofurans [31]. Our results also showed that iodine could promote efficiently these organic transformations as a cost effective, easily available, green, and eco-friendly catalyst [42-44]. Realizing the potential of 1-cyanocyclopropane-1-carboxylates as important building blocks, we embarked in a cycloisomerization strategy for the synthesis of 4-cyanofuran-3-carboxylate derivatives via the cleavage of the C-C bond (path b, Scheme 1) of the cyclopropane.

Inspired by this study, we herein disclose a novel approach for the construction of fully substituted furans from 1-cyanocyclopropane-1-carboxylates via the iodine/potassium carbonate-mediated ring-opening/cyclization/rearrangement domino reaction (Scheme 1, pathway b). Therefore, the reaction details were carefully investigated and depicted as follows.

2. Results and discussion

At the beginning of our study, the reaction of substrate 1a, prepared easily by treatment of 1- (2- (4-chlorophenyl) -2-oxoethyl) pyridin-1-ium bromide with ethyl 3- (4-chlorophenyl) -2-cyanoacrylate according to reported methods [45, 46], was used as a model reaction for evaluating the effect of the properties of inorganic bases and the amount of iodine on the reaction. The observed results are summarized in Table 1.

As can be seen, the combinational iodine/sodium hydroxide could not promote efficiently the cycloisomerization reaction after 24 h, just 13% in the yield (entry 1). Pleasingly, a moderate yield (ca. 60%) of the product 4-cyanofuran-3-carboxylate (2a) was obtained using the weak inorganic bases potassium carbonate or cesium carbonate with iodine (entries 2 and 3), the K₂CO₃/I₂ system gave the more acceptable result. Then our efforts further focused on the amount of K₂CO₃ and I₂, the yield was decreased sharply when the amount of K₂CO₃ was changed from 1.0 equiv. to 0.5 equiv. (Table 1, entry 4) in the presence of 1.0 equiv. iodine for 24 h. While 1.5 equiv. K₂CO₃ was used under above reaction conditions, the reaction was complete after 12 h and the isolated yield was improved slightly (64%, Table 1, entry 5). When the amount of K₂CO₃ was increased to 2.0-2.5 equiv., the reaction time was shortened to 8 h and the isolated yields were the best 90% and 89%, respectively (Table 1, entries 6 and 7). Further studies were continued in order to find suitable reaction conditions to accomplish this transformation, we found that, the reaction was carried out under simple conditions that K₂CO₃ (4 mmol) and substrate 1a (2 mmol) were added in 5 mL of solvent DMF at 110 ℃ for 10 h, a detectable decline in the yield of product 2a appeared when the loading of iodine was decreased from 1.0 equiv. to 0.5 equiv. (Table 1, entry 8). On the contrary, increasing the loading of iodine from 1.0 equiv. to 1.5 equiv. could not markedly accelerate this reaction, however, the reaction time was shortened to 7 h (Table 1, entry 9). Next, based on our previous report [31], toluene as a solvent was investigated for the improvement of the title reaction (Scheme 2), as a result, not only the product 2a was isolated in 56% of yield, but also a side-product 2a' was obtained in 29% of yield, which is identical product in the presence of iodine and trimethylamine using toluene as a solvent. The stronger base K₂CO₃ promoted mainly the C2-C3 bond cleavage of 2-aroyl-3- aryl-1-cyanocyclopropane-1-carboxylates in comparison with relatively mild and organic base triethylamine. The kinetic intermediate 3-cyano-4-ethoxy-1, 4-dioxo-1-aryl-3- (arylmetheyliumyl) butan-2-ide was obtained easily via stereoselective bond cleavage in the presence of the stronger inorganic base. Contrary to the stronger inorganic base, moderate organic base actually gave a stable and thermodynamics intermediate 3-cyano-4-ethoxy-1, 4- dioxo-1-aryl-3- (arylmetheyliumyl) butan-1-ide (Scheme 1). Additionally, the selective bond cleavage resulted in polar aprotic solvent DMF in comparison with nonpolar aprotic solvent toluene, may also be illustrated by the term of polarizability (Scheme 2).

These observations clearly indicate that the properties of the inorganic bases and iodine play an important role in this reaction. A series of experiments revealed that the optimal results were obtained when the reaction of 1-cyanocyclopropane-1-carboxylate (1a) together with 1.0 equiv. iodine and 2.0 equiv. K₂CO₃ was carried out in DMF, the resultant mixture was stirred for 8 h at 110 ℃, whereby the yield of 2a reached 90% (Table 1, entry 6).

With the optimal reaction conditions in hand, we began to explore the substrate scope of 1-cyanocyclopropane-1-carboxylates in this I₂/K₂CO₃ mediated ring-opening/cyclization/rearrangement domino reaction (Table 2). The results indicated that aromatic rings of 1-cyanocyclopropane-1-carboxylates containing electron-withdrawing or electron-donating groups were well tolerated and the desired substituted 4-cyanofuran-3-carboxylates could be afforded in moderate to good yields. In general, aromatic rings of 1-cyanocyclopropane-1-carboxylates bearing electronwithdrawing groups, including para- (1a, 1c, 1e, 1f, 1g), ortho- (1k), and meta- (1j) substituted positions, gave better results. Electrondonating group methoxy (1b, 1d, 1i, 1l) was also well tolerated under the optimized conditions. All corresponding substituted 4-cyanofuran-3-carboxylates were analyzed by their ¹H NMR, ¹³C NMR and MS (Supporting information).

On the basis of the above experimental results together with related reports, presumably the reaction seems to occur following the mechanistic pathway demonstrated in Scheme 3. First of all iodine polarized and activated the carbonyl group of arylketone [44] as it behaved as a mild Lewis acid [47]. In the first step iodine binded with the carbonyl group of arylketone to give an iodine- carbonyl complex [A] and thus increased the withdrawingelectron character of the carbonyl carbon of arylketone [48]. Then potassium carbonate promoted selectively the cleavage of the C-C bond (path b, Scheme 1) of the cyclopropane to form 3-cyano-4- ethoxy-1, 4-dioxo-1-aryl-3- (arylmetheyliumyl) butan-2-ide [B], Next, the tautomerism of butan-2-ide [B] formed an intermediate 2-cyano-2- (ethoxycarbonyl) - 1, 4-diarylbut-3-en-1-ylium-4-olate [C], which underwent an intramolecularly nuclophilic coupling on phenylmethylium ion to give a dihydrofuran intermediate [D]. The dihydrofuran intermediate [D] was transformed to the bicyclic cyclopropane[b]furan intermediate [E] via an intramolecular nucleophilic addition to the carbonyl group of ester again. Further the iodination at α-carbon of cyano group together with ring opening of cyclopropane and following ethoxycarbonyl-transfer reaction formed an intermediate 3-cyano-4- (ethoxycarbonyl) -3- iodo-2, 5-diaryl-3, 4-dihydro-2H-furan-1-ium [F]. In the presence of potassium carbonate the tautomerism of the an iododihydrofuran [F] formed ethyl 4-cyano-4-iodo-2, 5-diaryl-4, 5-dihydrofuran-3-carboxylate intermediate [G]. Finally, removal of HI and aromatization of the iododihydrofuran [G] resulted in the formation of the corresponding 4-cyano-3-furancarboxylates under basic conditions.

3. Conclusion

In conclusion, we have developed a straightforward and efficient approach for the synthesis of alkyl 4-cyanofuran-3- carboxylates via iodine/potassium carbonate-promoted ringopening/cyclization/rearrangement domino reaction of 1-cyanocyclopropane-1-carboxylates. The operational simplicity, ready availability of reactants, and good chemical yields make this novel synthetic method appealing in diversity-oriented synthesis. This protocol is expected to find considerable applications in the synthesis of polysubstituted furancarboxylates, which are a wide range of structurally interesting and pharmacologically significant compounds.

4. Experimental

All melting points were determined in a Yanaco melting point apparatus and are uncorrected. IR spectra were recorded in a Nicolet FT-IR 5DX spectrometer. The ¹H NMR (400 or 600 MHz) and ¹³C NMR (100 or 150 MHz) spectra were recorded in a Bruker AV-600 spectrometer with TMS as internal reference in CDCl₃ solutions. The J values are given in hertz. Only discrete or characteristic signals for the ¹H NMR are reported. The MS spectra were obtained on a ZAB-HS mass spectrometer with 70 eV. Flash chromatography was performed on silica gel (230-400 mesh) eluting with ethyl acetate-hexanes mixture. All reactions were monitored by thin layer chromatography (TLC). All reagents and solvents were purchased from commercial sources and purified commonly before used.

4.1. General procedure for preparation of 2, 5-diaryl-4-cyanofuran-3- carboxylates (2a-l)

The appropriate 2-aroyl-3-aryl-1-cyanocyclopropanecarboxylates (2 mmol), potassium carbonate (552 mg, 4 mmol) and iodine (510 mg, 2 mmol) were dissolved in 5 mL of DMF, and the resultant mixture was stirred at room temperature for 15 min. The reaction mixture was stirred at 110 ℃ for 8 h, and the completion of reaction was confirmed by TLC (EtOAc/hexanes 1:15). Subsequently, the solvent was removed under reduced pressure, to the residues was added with water (10 mL) followed by extraction with dichloromethane (10 mL × 2). The organic phase was washed with water (15 mL) and brine (10 mL), and dried over anhydrous sodium sulfate. After removal of dichloromethane, the crude product was purified by flash chromatography (silica gel, EtOAc/hexanes, 1/50) to give the desired 2a-l.

Ethyl 2, 5-bis (4-chlorophenyl) -4-cyanofuran-3-carboxylate (2a) : White solid, 90%; mp 171.2-171.9 ℃ (EA/PE); IR (KBr, cm^-1) : v 3433, 3106, 2981, 2936, 2232, 1712, 1594, 1483, 1401, 1368, 1327, 1222, 1157, 1103, 1017, 969, 833, 785, 711, 672, 483; ¹H NMR (400 MHz, CDCl₃) : δ 7.92 (d, 2H, J = 8.8 Hz), 7.86 (d, 2H, J = 8.8 Hz), 7.40 (d, 2H, J = 8.8 Hz), 7.38 (d, 2H, J = 8.8 Hz), 4.33 (q, 2H, J = 7.2 Hz), 1.34 (t, 3H, J = 7.2 Hz); ¹³C NMR (CDCl₃, 100 MHz) : δ 160.9, 157.9, 155.9, 137.0, 136.8, 130.0, 129.5, 128.7, 127.0, 126.1, 125.5, 115.2, 113.5, 94.4, 61.9, 13.9; MS (EI) (m/z) : 408.02 [(M+Na)⁺] (100%).

Acknowledgments

Financial support of this research by the National Natural Science Foundation of China (NSFC No. 21173181) is gratefully acknowledged by authors. A Project was funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.cclet.2016.09.017.