Gold(I)-Catalyzed Domino Reaction for Furopyrans Synthesis

We report herein an efficient synthesis of furopyran derivatives through a gold(I)-catalyzed domino reaction. The cascade reaction starts with two regioselective cyclizations, a 5-endo-dig and a 8-endo-dig, followed with a Grob-type fragmentation and a hetero Diels–Alder. The obtained furopyran derivatives contain fused and spiro-heterocycles. During this one-pot process, four bonds and four controlled stereogenic centers including a quaternary center are formed.

In this context, we have previously reported the synthesis of polycyclic molecules containing furopyran cores through a gold(I)-catalyzed domino reaction (Scheme 1) [24,25]. Particularly, we have described the synthesis of two classes of furopyrans, 2 and 3, starting from the same source 1 and only changing the solvent of the reaction. 4a (64%, Entry 1, Table 1). We then decided to explore other common dienophiles [2] in order to increase the complexity of such scaffolds. The use of 4-phenylbut-3-yn-1-ol was motivated by obtaining the in situ formation of the 5-phenyl-2,3-dihydrofuran able to react as a dienophile in the reaction (entry 2) [20]. We obtained the formation of 5a with 7% yield. With dihydropyran, the conversion was total, and the protected alcohol 6 was not isolated completely purely (around 20% yield) in the middle of an unidentified product (entry 3). Surprisingly, methyl or ethyl vinyl ether gave complete conversion into a complex mixture (entries 4 and 5). The same result was observed with dihydropyrrole (entry 6), phenyl vinyl thioether (entry 7) and furan-2,5-dione (entry 8). 4a (64%, Entry 1, Table 1). We then decided to explore other common dienophiles [2] in order to increase the complexity of such scaffolds. The use of 4-phenylbut-3-yn-1-ol was motivated by obtaining the in situ formation of the 5-phenyl-2,3-dihydrofuran able to react as a dienophile in the reaction (entry 2) [20]. We obtained the formation of 5a with 7% yield. With dihydropyran, the conversion was total, and the protected alcohol 6 was not isolated completely purely (around 20% yield) in the middle of an unidentified product (entry 3). Surprisingly, methyl or ethyl vinyl ether gave complete conversion into a complex mixture (entries 4 and 5). The same result was observed with dihydropyrrole (entry 6), phenyl vinyl thioether (entry 7) and furan-2,5-dione (entry 8). 4a (64%, Entry 1, Table 1). We then decided to explore other common dienophiles [2] in order to increase the complexity of such scaffolds. The use of 4-phenylbut-3-yn-1-ol was motivated by obtaining the in situ formation of the 5-phenyl-2,3-dihydrofuran able to react as a dienophile in the reaction (entry 2) [20]. We obtained the formation of 5a with 7% yield. With dihydropyran, the conversion was total, and the protected alcohol 6 was not isolated completely purely (around 20% yield) in the middle of an unidentified product (entry 3). Surprisingly, methyl or ethyl vinyl ether gave complete conversion into a complex mixture (entries 4 and 5). The same result was observed with dihydropyrrole (entry 6), phenyl vinyl thioether (entry 7) and furan-2,5-dione (entry 8). 4a (64%, Entry 1, Table 1). We then decided to explore other common dienophiles [2] in order to increase the complexity of such scaffolds. The use of 4-phenylbut-3-yn-1-ol was motivated by obtaining the in situ formation of the 5-phenyl-2,3-dihydrofuran able to react as a dienophile in the reaction (entry 2) [20]. We obtained the formation of 5a with 7% yield. With dihydropyran, the conversion was total, and the protected alcohol 6 was not isolated completely purely (around 20% yield) in the middle of an unidentified product (entry 3). Surprisingly, methyl or ethyl vinyl ether gave complete conversion into a complex mixture (entries 4 and 5). The same result was observed with dihydropyrrole (entry 6), phenyl vinyl thioether (entry 7) and furan-2,5-dione (entry 8). 4a (64%, Entry 1, Table 1). We then decided to explore other common dienophiles [2] in order to increase the complexity of such scaffolds. The use of 4-phenylbut-3-yn-1-ol was motivated by obtaining the in situ formation of the 5-phenyl-2,3-dihydrofuran able to react as a dienophile in the reaction (entry 2) [20]. We obtained the formation of 5a with 7% yield. With dihydropyran, the conversion was total, and the protected alcohol 6 was not isolated completely purely (around 20% yield) in the middle of an unidentified product (entry 3). Surprisingly, methyl or ethyl vinyl ether gave complete conversion into a complex mixture (entries 4 and 5). The same result was observed with dihydropyrrole (entry 6), phenyl vinyl thioether (entry 7) and furan-2,5-dione (entry 8). obtaining the in situ formation of the 5-phenyl-2,3-dihydrofuran able to react as a dienophile in the reaction (entry 2) [20]. We obtained the formation of 5a with 7% yield. With dihydropyran, the conversion was total, and the protected alcohol 6 was not isolated completely purely (around 20% yield) in the middle of an unidentified product (entry 3). Surprisingly, methyl or ethyl vinyl ether gave complete conversion into a complex mixture (entries 4 and 5). The same result was observed with dihydropyrrole (entry 6), phenyl vinyl thioether (entry 7) and furan-2,5-dione (entry 8). and 4c and 4d were isolated with 60% yield. Results are more disparate with halogen substitutions, where yields between 28 to 70% were obtained (4e-4i). As described previously, with ortho-substituted aryl groups, the steric hindrance hampers the reaction. Indeed, with an ortho-chloro substituted aryl, less than 5% of 4 was observed. With aryls exhibiting electron-withdrawing groups such as CF 3 and NO 2 , yields between 34 and 60% (4j-4l) were obtained. Heteroaromatics such as thiophene and benzothiophene gave good results (4m-4n, more than 65%).

Scheme 3.
Scope of the reaction.

Conclusions
In conclusion, we have described the synthesis of new 4H-furo[2,3-b]pyrans 4 via a gold-catalyzed domino reaction. The sequence includes two regioselective cyclizations, a 5-endo-dig and a 8-endo-dig, followed with a Grob-type fragmentation and a hetero Diels-Alder reaction. A total of 14 compounds have been described and isolated, with yields ranging between 28-80%.

General Information
All reagents, chemicals and dry solvents were purchased from commercial sources and used without purification. When mentioned that the reaction was conducted in dry media, glassware dried for several hours at 110 • C in an oven was used. Triethylamine (Et 3 N) and diisopropylamine (DIPA) were distilled from KOH in an S-tube prior to each experiment in which they were involved. Reactions were monitored by TLC (thin layer silica gel chromatography) using Merck silica gel 60 F254 on aluminum sheets. TLC plates were visualized under UV light and revealed with acidic p-anisaldehyde stain or KMnO 4 stain. Crude products were purified by flash column chromatography on Merck silica gel Si 60 (40-63 µm). NMR spectra were recorded in CDCl 3 on a Bruker Avance III BBFO+ probe spectrometer 400 MHz for 1 H analyses and 100 MHz for 13 C analyses. Proton chemical shifts are reported in ppm (δ), relatively to residual CHCl 3 (δ 7.26 ppm). Multiplicities are reported as follows: singlet (s), doublet (d), triplet (t), quartet (q), quintet (quint), broad singlet (bs), broad doublet (bd) combinations or multiplet (m). Coupling constant values J are given in Hz. Carbon chemical shifts are reported in ppm (δ), relative to the internal standard CDCl 3 (δ 77.23 ppm). 1 H and 13 C NMR signals were assigned mostly on the basis of 2D-NMR (COSY, HSQC, HMBC) experiments. High resolution mass spectral analyses (HRMS) were performed using an Agilent 1200 RRLC HPLC chain and an Agilent 6520 Accurate mass QToF. Infrared spectra (IR) were recorded on a FTIR Thermo Nicollet ATR 380, Diamant Spectrometer.

Synthesis of 1f and 1g
Anhydrous THF and distilled Et 3 N were mixed in a 2-necked flask under argon. The iodoaryl (1.5 eq.), PdCl 2 (PPh 3 ) (0.03 eq.) and CuI (0.06 eq.) were added to the flask and this mixture was degassed with argon for 15 min. The alkyne (1 eq.) was dissolved in THF degassed with argon for 15 min and added to the 2-necked flask. The mixture was stirred overnight at room temperature (20 • C) and monitored by TLC (9/1 pent/Et 2 O). Once the TLC showed complete conversion of the true alkyne, the reaction mixture was filtered through a pad of Celite with CH 2 Cl 2 as eluent and concentrated to give the crude product as a dark-brown solid. The latter was purified by flash column chromatography (98/2 pent/Et 2 O) to afford the pure tert-butyldimethylsilyl-protected coupling product. TBAF (1 eq.) was added to a solution of this latter protected product in THF at 0 • C. This mixture was stirred at room temperature until the TLC (9/1 pent/Et 2 O) showed complete conversion of the starting material. The reaction mixture was dissolved in a saturated aqueous NH 4 Cl solution. The aqueous phase was extracted with CH 2 Cl 2 . The gathered organic layers were dried over MgSO 4 , filtered and concentrated to afford the crude as a yellowish oil. The latter was purified by flash column chromatography (6/4 pent/Et 2 O) to afford the pure deprotected compound (1f and 1g).