Bifunctionalized Allenes. Part XVI. Synthesis of 3-Phosphoryl-2,5-dihydrofurans by Coinage Metal-Catalyzed Cyclo-isomerization of Phosphorylated α-Hydroxyallenes

Phosphorylated α-hydroxyallenes 1 and 2 were smoothly converted into the corresponding 2,5-dihydrofurans 3 and 4 in an 5-endo-trig cycloisomerization reaction by using 5 mol % of coinage metal salts as catalyst. Experimental conditions such as the type of the solvent, the reaction temperature, the mol % and the type of the catalyst were optimized. This mild and efficient cyclization method can be applied to dimethyl 1-hydroxyalkyl-alka-1,2-dienephosphonates 1 and 2-diphenylphosphinoyl-2,3-dien-1-ols 2a–c and 3-diphenylphosphinoyl-3,4-dien-2-ols 2d,e, furnishing 3-phosphorylated 2,5-dihydrofurans 3 and 4 in very good yields.


Introduction
2,5-Dihydrofurans and their derivatives are structural subunits frequently found in a wide variety of natural products which find application as flavor and fragrance compounds and pharmaceuticals [1][2][3] OPEN ACCESS and represent pivotal structural elements in a wide variety of different biologically active molecules. For instance, they can be found in mycotoxins such as verrucosidine [4] and the structurally related citreoviridine [5], as well as vitamin A metabolites [6], polyether antibiotics [7,8], spiroketals [9] and even amino acids [10]. 2,5-Dihydrofurans are also important intermediates in organic synthesis due to the presence of the C=C bond as well as the five-membered ring. Consequently, much attention has been paid to the development of efficient and diverse synthetic methods for construction of this five-membered ring system [11][12][13].
On the other hand, the literature data on the reactions of phosphorylated allenes with electrophilic reagents reveal that the reactions proceed with cyclization of the allenic system bearing the phosphoryl group (O=P-C=C=C) to give heterocyclic compounds in most cases and the outcome depends on the structure of the starting allenic compound as well as the type of electrophile used [41][42][43][44]. Several diethylphosphono-substituted α-allenic alcohols [45] and glycols [46] were prepared by Brel [47,48] directly from alcohols by Horner-Mark rearrangement of unstable propargylic phosphites and used as starting materials for study of the cyclization in the presence of AgNO3 [46,47,49] and CuCl2 [48].
Our long-standing research program focuses on the development of efficient cyclization reactions of 1,1-[50,51] and 1,3-bifunctionalized allenes [52,53]. More specifically, our attention is drawn to phosphorylated hydroxyallenes as 1,1-bifunctionalized allenes that comprise a phosphoryl and a hydroxyalkyl group. The applications of these groups as temporary transformers of chemical reactivity of the allenic system in the synthesis of eventually heterocyclic compounds are of particular interest. These molecules can be considered a combination of an allenephosphonate or allenyl phosphine oxide and a hydroxyallene and they are supposed to have different reactivity profiles in cycloisomerization reactions. Our recent research has led to a significant result, whereby we have developed a convenient and efficient method for the regioselective synthesis of phosphorylated α-hydroxyallenes using an atom economical [2,3]-sigmatropic rearrangement [54]. In this paper, we present recent results of ongoing studies dedicated towards the optimization of the experimental conditions and the catalyst efficiency in the coinage metal salts-catalyzed cycloisomerization of α-hydroxyalkyl-allenephosphonates and phosphine oxides to 3-phosphorylated 2,5-dihydrofurans, which strongly improve the scope of this method.

Results and Discussion
In addition to our previously reported preparation [55] of 2,5-dihydro-1,2-oxaphospholes by electrophilic cyclization of the 1-hydroxyalkyl-allenephosphonates 1 and allenyl phosphine oxides 2 due to the participation of the phosphonate neighboring group in the 5-endo-trig cyclization, we carried out the cycloisomerization reaction of the abovementioned compounds 1 and 2 in the presence of coinage metal salts as catalysts. Our initial work began with the cycloisomerization reaction of the model α-hydroxyalkyl-allenephosponate 1а with AgNO3 in order to optimize the reaction conditions such as the influence of the solvent, the reaction temperature, the mol % and the type of the catalyst. The reaction occurred with formation of the dimethyl (5-ethyl-5-methyl-2,5-dihydrofuran-3-yl) phosphonate (3a, Scheme 1). The results are summarized in Table 1.  At the very beginning, the reaction occurred in 1,2-dichloroethane at −20 °C with 10 mol % of catalyst (Table 1, entry 1). The yield was 41%. On the other hand, when we used 5 mol % of catalyst to carry out the reaction at 0 °C or room temperature in the same solvent the yield increased considerably (Table 1, entries 2 and 3). Lower yield was obtained at reflux in the same solvent (Table 1, entry 4). It is obvious that the optimal temperature for the cycloisomerization reaction of compound 1а is room temperature. The use of polar solvents such as chloroform, ethanol, acetonitrile and THF at room temperature with 5 mol % AgNO3 produces the product in relatively good yields (Table 1,

entries 5-8).
A lower yield occurred in toluene (Table 1, entry 9). When the solvent was a mixture of acetone and H2O [15] at room temperature the yield was 77% with 5 mol % of catalyst (Table 1, entries 11 and 12). The data confirm that the optimal conditions for cycloisomerization of model compound 1а (Table 1, entry 14) are methylene chloride, 5 mol % catalyst and room temperature. We found that reactions occurring at low or high reaction temperatures different from the optimum afford lower yields (Table 1, entries 2, 4 and 13). We also saw a lower yield when we used 10 mol % of catalyst at room temperature in dichloromethane ( Table 1, entry 15). The type of catalyst and its influence on the yields of the cycloisomerization products of the α-hydroxyalkyl-allenephosphonates 1a-e was also of great interest to us. We thus conducted a series of experiments to optimize the reaction conditions of the model compound 1а (Scheme 2). We applied the following coinage metal salts as catalysts: AgNO3, AgClO4, AuCl, AuCl3, ZnCl2, NiCl2, PtCl2, SnCl2, AlCl3, PdCl2, Pd(PPh3)4, CuCl2, CuCl, CuBr, and CuI. The data reveal that both Au and Ag are excellent catalysts. Pd, Cu(II) and Pt are very good catalysts for our experiments. It becomes obvious that Zn, Ni, Sn and Al are relatively good catalysts. It is the Cu(I) catalysts that are bad. Table 2 presents the characteristics of all the above-mentioned catalysts in the cycloisomerization reaction of the model compound 1а.
The next step in our study was to explore the possibilities of the cycloisomerization reactions of the α-hydroxyalkyl-allenyl phosphine oxides 2а-e synthesized by us. At the very beginning, we used 2-diphenylphosphinoyl-4-methylhexa-2,3-dien-1-ol (2a) as a model compound. The optimal cycloisomerization conditions included dichloromethane as solvent, 5 mol % catalyst and room temperature. The reaction occurred via an 5-endo-trig cyclization to give 4-(diphenylphosphinoyl)-2ethyl-2-methyl-2,5-dihydrofuran (4а, Scheme 2). We performed a series of experiments with the sole intention of determining the best catalysts bearing in mind two criteria-highest yield and shortest reaction time. The model compound 2а reacts with the catalysts shown in Table 2, in which the yields obtained and the reaction time of the preparation of isomer 4а are presented. The experimental data reveals that the best catalytic characteristics correspond to Au, Ag and Pd catalysts ( Table 2). The Cu(II), Zn and Pt catalysts that show very good results. The Sn, Al and Ni are relatively good. The investigation on the cycloisomerization reaction of the synthesized series of α-hydroxyalkylallenephosphonates 1a-e was intended to be systematical. We applied the optimized reaction temperature, type of the solvent and molar ratio of the catalyst conditions in regard to the substrate. Having in mind that gold catalysts are expensive and sensitive to moisture, we decided to use AgClO4 as a main catalyst in cycloisomerization reaction in order to extend our study (Scheme 3). The results are explicit enough-a catalytic 5-endo-trig cycloisomerization occurs and the hydroxy group participates as an internal nucleophile to give the 2,5-dihydrofuran-3-yl phosphonates 3 in very good yields. Our study was systematized also on the cycloisomerization of a series of α-hydroxyalkyl-allenyl phosphine oxides 2a-e in methylene chloride at room temperature (Scheme 3). Moreover, it was the AgClO4 catalyst, which is easily accessible and relatively good, that was used in our research. The results are undisputable-the 3-diphenylphosphinoyl-2,5-dihydrofurans 4 are produced as a result of the participation of the neighboring hydroxy group as an internal nucleophile in the cyclization process. Table 3 shows the reaction times and yields of the cycloisomerization reaction of the α-hydroxyalkyl-allenephosphonates 1a-e and allenyl phosphine oxides 2a-e.

General Information
All new synthesized compounds were purified by column chromatography and characterized on the basis of NMR, IR, and microanalytical data. NMR spectra were recorded on DRX Bruker Avance-250 (Bruker BioSpinGmbH, Karlsruhe, Germany) ( 1 H at 250.1 MHz, 13 C at 62.9 MHz, 31 P at 101.2 MHz) and Bruker Avance II+600 (Bruker BioSpinGmbH) ( 1 H at 600.1 MHz, 13 C at 150.9 MHz, 31 P at 242.9 MHz) spectrometers for solutions in CDCl3. All 1 H-and 13 C-NMR experiments were measured referring to the signal of internal TMS and 31 P-NMR experiments were measured referring to the signal of external 85% H3PO4. J values are given in Hertz. IR spectra were recorded with an Afinity-1 FT-IR spectrophotometer (Shimadzu, Tokyo, Japan). Elemental analyses were carried out by the Microanalytical Service Laboratory of Faculty of Chemistry and Pharmacy, University of Sofia, Sofia, Bulgaria, using Vario EL3 CHNS(O) (Elementar Analysensysteme, Hanau, Germany). Column chromatography was performed on Kieselgel F25460 (70-230 mesh ASTM, 0.063-0.200 nm, Merck, Darmstadt, Germany). Reactions were carried out in oven dried glassware under an argon atmosphere and exclusion of moisture. All compounds were checked for purity on Kieselgel F25460 TLC plates (Merck).

Starting Materials
The starting phosphorylated α-hydroxyallenes 1 and 2 were prepared according to the established procedure [54]. CH2Cl2 was distilled over CaH2 and other organic solvents used in this study were dried over appropriate drying agents by standard methods and distilled prior to use. All other chemicals used in this study were commercially available and were used without additional purification unless otherwise noted.

General Procedure for the C Co oi in na ag ge e Metal-catalyzed Cycloisomerization of the 1-Hydroxyalkyl-1,2-dienephosphonates 1
Metal salt catalyst (0.15 mmol) was added to a solution of the 1-hydroxyalkyl-1,2dienephosphonate 1 (3.0 mmol) in dry dichloromethane (10 mL). The mixture was stirred at room temperature and in the dark for the minutes indicated in the Table 3. Saturated sodium chloride solution was added to precipitate the silver ions. The product was extracted by chloroform. The organic layer was dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was chromatographed on a column (silica gel, Kieselgel Merck 60 F254) with a mixture of ethyl acetate and hexane (6:1) as an eluent to give the pure products 3 as oils, which had the following properties:

Conclusions
In conclusion, we have developed a coinage metal-catalyzed cycloisomerization of phosphorylated α-hydroxyallenes, which provides an efficient route to 3-phosphorylated 2,5-dihydrofurans. Due to the ready availability of the starting materials and the catalyst, the convenient operation and mild conditions (room temperature, short reaction time), the very good yields and the usefulness of the resulting 2,5-dihydrofuran products, the reaction shows potential and will be useful in organic synthesis as well in the application of the method in target-oriented synthesis. Further investigation on the chemistry of other phosphorylated allenols for the synthesis of different heterocyclic systems is being intensively carried out in our laboratory. Moreover, results of an initial investigation of the biological activity of the compounds prepared were encouraging, and the antibacterial and antifungal activities of selected compounds are now under investigation in our University.

Author Contributions
V.C.C. proposed the subject, designed the study and offered necessary guidance to I.E.I. and I.K.I. V.C.C. and I.K.I. conceived and designed the experiments. I.E.I. and I.K.I. performed the experiments under the supervision of the lead author V.C.C. who analyzed the spectral data and wrote the manuscript.