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Article

Gold-Catalyzed Propargylic Substitution Followed by Cycloisomerization in Ionic Liquid: Environmentally Friendly Synthesis of Polysubstituted Furans from Propargylic Alcohols and 1,3-Dicarbonyl Compounds

by
Hitomi Chiaki
,
Yoshimitsu Hashimoto
and
Nobuyoshi Morita
*
Department of Pharmacy, Showa Pharmaceutical University, Machida 194-8543, Japan
*
Author to whom correspondence should be addressed.
Molecules 2024, 29(22), 5441; https://doi.org/10.3390/molecules29225441
Submission received: 2 October 2024 / Revised: 8 November 2024 / Accepted: 14 November 2024 / Published: 18 November 2024
(This article belongs to the Special Issue New Metal Catalysts for Sustainable Chemistry)
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Abstract

:
Gold-catalyzed propargylic substitution of propargylic alcohols 1 with 1,3-dicarbonyl compounds 2 followed by cycloisomerization in ionic liquid enables the environmentally friendly synthesis of polysubstituted furans 3 in good-to-high yields. The reaction proceeds via the hydrated propargylic substitution product 3″aa. The gold catalyst can be recycled at least three times.

1. Introduction

Polysubstituted furans are frequently found as structural components of natural products [1] and biologically active compounds [2,3,4] and are also useful as reagents and intermediates [5,6] in organic synthesis. Therefore, various synthetic methods have been developed by many chemists over a long period of time [7,8,9]. One of many procedures for the synthesis of polysubstituted furans involves the powerful approaches of transition-metal-catalyzed propargylic substitution followed by cycloisomerization (Scheme 1).
For example, the efficient synthesis of polysubstituted furans 3 was achieved via a propargylic substitution/cycloisomerization sequence from propargylic alcohols 1A and 1,3-dicarbonyl compounds 2 using a combination of transition metals and reagents (Ag/Cs2CO3 [10], Ir-Sn/Cs2CO3 [11]). On the other hand, Arcadi reported the gold-catalyzed propargylic substitution [12] of propargylic alcohol 1A followed by cycloisomerization to produce polysubstituted furans 3 [13]. We also reported the synthesis of polysubstituted furans 3 via propargylic substitution/cycloisomerization sequence from propargylic amides 1B using a gold catalyst [14]. However, these methodologies using a transition metal catalyst/reagent combination [10,11] and gold catalysts [13,14] require toxic halogenated or volatile organic solvents, making it essential to avoid the use of organic solvents and to reuse catalysts to reduce environmental impact and develop sustainable chemical synthesis methods.
One of the ways to achieve sustainable chemical synthesis [15,16] is to use ionic liquids instead of organic solvents [17,18,19,20,21,22,23,24,25,26]. Ionic liquids have the following features: (1) non-volatility; (2) high solubility in many organic compounds as well as transition metal catalysts; (3) easy extraction of the products in ionic liquids with non-polar organic solvents; and (4) recyclability of transition metal catalysts in ionic liquids. For these reasons, ionic liquids are used as an alternative solvent to organic solvents.
Recently, we developed the environmentally friendly and stereoselective synthesis of 1,2,3-trisubstituted indanes and 2,3-dihydrobenzofurans by gold(I)/(III) catalysts in ionic liquid [27,28,29] or water [30]. In these methods, environmentally friendly ionic liquid or water is used as a solvent, gold-catalyzed reactions for synthesis of cyclic compounds are achieved, and the gold catalysts in the ionic liquids are successfully reused.
Continuing our research of sustainable chemical synthesis methods, we focused on the gold-catalyzed synthesis of polysubstituted furans in ionic liquid [17,18]. Herein, we present a gold-catalyzed propargylic substitution with 1,3-dicarbonyl compounds followed by cycloisomerization for the environmentally friendly synthesis of polysubstituted furans. The advantages of this approach from an environmental and economic point of view are that it does not use toxic or volatile solvents, does not require stoichiometric amounts of reagents, and allows the gold catalyst in the ionic liquid to be reused several times.

2. Results and Discussion

We first examined propargylic substitution of propargylic alcohol 1a with acetylacetone (2a) followed by cycloisomerization in the presence of an oxophilic gold(III) catalyst to activate the hydroxyl group at the propargylic position (Table 1). Treatment of propargylic alcohol 1a with acetylacetone (2a) in the presence of gold(III) catalyst (5 mol% AuBr3) at room temperature for 3 days in an ionic liquid, [ethylmethylimidazolium (EMIM)][NTf2], afforded the desired furan 3aa in low yield (entry 1). The yield of 3aa was improved to 72% yield when the reaction was carried out with the addition of a silver catalyst (15 mol% AgOTf) to activate the gold catalyst (entry 2). In an attempt to further improve the yield, the reaction was carried out at 100 °C for 30 min, but the yield of the desired furan 3aa decreased (entry 3). However, reducing the reaction temperature from 100 °C to 60 °C afforded 3aa in 84% yield (entry 4). When the amount of acetylacetone (2a) was increased from 1 eq. to 3 eq., the yield of the desired furan 3aa decreased slightly (entry 5). In contrast to the reaction using gold(III) catalyst, the reaction in the presence of gold(I) catalyst (5 mol% AuCl or 5 mol% AuCl with 5 mol% AgOTf) was less effective (entries 6 and 7).
Next, the effect of the counter anion of the silver catalyst (AgNTf2, AgBF4, AgSbF6) was investigated (Table 2). Treatment of propargylic alcohol 1a with acetylacetone (2a) in the presence of AuBr3 (5 mol%) with AgNTf2 (15 mol%) or AgBF4 (15 mol%) in [EMIM][NTf2] at 60 °C afforded the corresponding furan 3aa in moderate yield, 57% or 47%, respectively (entries 2 and 3). The use of AgSbF6 (15 mol%) in the reaction failed to generate the desired product 3aa (entry 4).
To examine the effect of the ionic liquid, we conducted reactions with [EMIM][CH3CO2], [EMIM][Me2PO4], [EMIM][HSO4], [EMIM][MeSO4], and [EMIM][OTf] (Table 3). With [EMIM][CH3CO2] or [EMIM][Me2PO4], the reaction did not proceed at all (entries 2 and 3). [EMIM][HSO4], [EMIM][MeSO4] and [EMIM][OTf] afforded trace amounts of the desired furan 3aa (entries 4–6). The use of an organic solvent, dichloroethane (ClCH2CH2Cl), instead of [EMIM][NTf2] reduced the yield of 3aa (entry 7). These experiments showed that [EMIM][NTf2] is the preferred solvent for this transformation.
Lee’s group reported various advantages of ionic liquids for catalytic reactions, including the formation of more reactive catalysts and the stabilization of reactive intermediate and transition states [31]. The exact reason for the activity of AuBr3 and AgOTf in ionic liquids is still unclear, but two possibilities related to the formation of the active gold species, Au(NTf2)3 and NHC-Au species (NHC = N-Heterocyclic Carbene ligand) can be considered. The first possibility is the formation of an active gold species, Au(NTf2)3, which is generated from the exchange reaction between the chloride ion of the gold catalyst and the NTf2 ion of the ionic liquid, [EMIM][NTf2]. The second possibility is the formation of an active NHC–gold species. This active species might be generated from the EMIM cation of [EMIM][NTf2]. The possibility for the generation of this type of active species has been reported by other groups [32,33] and might also be possible with gold catalysts.
We next investigated the scope and limitations of this procedure for the synthesis of polysubstituted furans 3 by using propargylic alcohol 1a with various 1,3-dicarbonyl compounds 2a–e in the presence of 5 mol% AuBr3 and 15 mol% AgOTf in [EMIM][NTf2] (Figure 1). Various combinations of propargylic alcohol 1a with 1,3-dicarbonyl compounds 2a–e afforded the corresponding products 3 in good to high yields. The reaction proceeded not only with 1,3-diketones 2a and 2b, but also with β-ketoesters 2c–e, although the yield of furan 3 was somewhat lower with β-ketoesters 2c–e.
To investigate the scope and limitations of this procedure, we tried the reaction of propargylic alcohol 1b bearing a methyl group at the propargylic position instead of a phenyl group. However, the reaction with 1b afforded a complex mixture (Scheme 2). This result suggests that the phenyl group at the propargylic position is essential for the formation of polysubstituted furans 3.
Next, we attempted the reaction of propargylic alcohol 1c bearing a hexyl group at the terminus of acetylene instead of a phenyl group. The reaction of 1c resulted in a low yield of the corresponding polysubstituted furan 3ca (Scheme 3).
We next investigated the reaction of propargylic alcohol 1d without substituent (R = H) on the terminal of acetylene (Scheme 4). Treatment of 1d with acetylacetone (2a) in the presence of AuBr3 (5 mol%) and AgOTf (15 mol%) in [EMIM][NTf2] at 60 °C for 30 min afforded the corresponding furan 3ea in 38% yield. On the other hand, the reaction with propargylic alcohol 1e bearing a trimethylsilyl group (R = TMS) gave the product 3ea in high yield, with desilylation (Scheme 4). Additionally, it was observed that the reaction was faster for substrates with silyl group than for those with phenyl group (reaction time; 1a: 30 min/1e: 10 min). This is probably due to the β-cation-stabilizing effect [34,35] of the silyl group, which would promote cycloisomerization (see Scheme 7). This phenomenon was also observed in our previous work [14].
Next, we investigated the scope and limitations of this procedure for the synthesis of polysubstituted furans 3 by using propargylic alcohol 1e and 1f bearing a silyl group at the terminal position of acetylene with various 1,3-dicarbonyl compounds 2a–e in the presence of 5 mol% AuBr3 and 15 mol% AgOTf in [EMIM][NTf2] (Figure 2). The reaction proceeded smoothly to give the corresponding furans 3 in good to high yields. In addition, the reaction was found to be faster than with a phenyl group at the terminus of acetylene for all substrate combinations; the reaction proceeded within 10 min.
Next, a large-scale preparation of polysubstituted furan 3fa was conducted (Scheme 5), using 1.0 g (3.9 mmol) of propargylic alcohol 1f and acetylacetone (2a), affording the corresponding product 3fa in 95% yield.
The reuse of the gold catalyst in ionic liquid is of great importance from both an environmental and economic point of view. Fortunately, the gold catalyst (5 mol% of AuBr3 15 mol% of AgOTf/ionic liquid [EMIM][NTf2]) could be recycled at least three times for the reaction of 1f with acetylacetone (2a) with only slight loss of activity (Table 4).
To confirm the reaction pathway, we examined the reaction of propargylic alcohol 1a with acetylacetone (2a) in the presence of AuBr3 (5 mol%) and AgOTf (15 mol%) in [EMIM][NTf2] at room temperature for 30 min. This afforded propargylic substitution product 3′aa and hydrated propargylic substitution product 3″aa in 10% and 83% yields, respectively (Scheme 6, eq. 1). NMR spectroscopic data supported the formation of 3″aa, and the structure was confirmed by means of X-ray crystal-structure analysis [36] (Scheme 6, eq. 1). Furthermore, the reaction of 3′aa with 1 eq. of water in the presence of AuBr3 (5 mol%) and AgOTf (15 mol%) in [EMIM][NTf2] at room temperature for 30 min afforded 3″aa and furan 3aa in 86% and 13% yields, respectively, while the reaction without water gave neither 3″aa nor 3aa [37] (Scheme 6, eq. 2). Finally, the reaction of 3″aa in the presence of AuBr3 (5 mol%) and AgOTf (15 mol%) in [EMIM][NTf2] at 60 °C for 30 min furnished the corresponding furan 3aa in good yield (Scheme 6, eq. 3). These results clearly indicate that the reaction proceeds via 3′aa and 3″aa.
A plausible reaction mechanism of gold(III)-catalyzed synthesis of polysubstituted furan 3aa via propargylic substitution followed by cycloisomerization is shown in Scheme 7. There are two possible pathways for the formation of propargylic substitution product 3′aa via propargylic substitution from propargylic alcohol 1a and acetylacetone (2a). First, the activation of the gold catalyst by coordination to the triple bond and the oxygen atom in propargylic alcohol 1a may promote the propargylic substitution (Scheme 7, path a). The second possibility is a propargylic substitution involving an active gold enolate species A [38,39,40,41,42,43,44]. That is, the reaction of gold catalyst with acetylacetone (2a) would produce a gold enolate species A, which coordinates to the triple bond and oxygen atom of the propargylic alcohol 1a, thereby facilitating the propargylic substitution to furnish the propargylic substitution product 3′aa (Scheme 7, path b). After completing the propargylic substitution, the gold catalyst would coordinate to the triple bond of the propargylic substitution product 3′aa, resulting in the cyclization to afford the vinyl gold complex B (3′aa → B). Cyclic vinyl gold complex B would be opened by the addition of a water molecule to furnish the gold complex E, which undergoes deauration to give the dehydrated propargylic substitution product 3″aa (B → C → D → E → 3″aa). Finally, coordination of the gold catalyst to the carbonyl group in the intermediate 3″aa would enable cycloisomerization, yielding the furan 3aa (3″aa → 3″aa-Au → F → G → H → 3aa). This sequential reaction has been observed to be dramatically faster when the substituent on the triple bond of propargylic alcohols 1e and 1f is a silyl group (R = TMS) than when it is a phenyl group. This is probably due to the β-cation-stabilizing effect B‘ [34,35] of the silyl group (TMS) on the acetylene in the cyclization from the propargylic substitution product 3′aa.

3. Materials and Methods

3.1. General Information

1H and 13C NMR spectra were recorded with a JEOL JNM-ECZ400S (Japan Electron Optics Laboratory Co., Ltd., Tokyo, Japan) or Bruker AV-400NEO spectrometer (Bruker, Billerica, MA, USA) at room temperature, with tetramethylsilane as an internal standard (CDCl3 solution). Chemical shifts were recorded in ppm, and coupling constants (J) in Hz. Infrared spectra (IR) were measured on an IR spectrometer (Shimadzu IRSpirit; Shimadzu Corporation, Kyoto, Japan) and are reported in wavenumbers (cm−1). Mass spectra were recorded on JEOL JMS-700 spectrometers (Japan Electron Optics Laboratory Co., Ltd., Tokyo, Japan). Merck silica gel 60 (1.09385) (Merck, Darmstadt, Germany) and Merck silica gel 60 F254 (Merck, Darmstadt, Germany) were used for column chromatography and thin layer chromatography (TLC), respectively.

3.2. General Procedure for Gold(III)-Catalyzed Propargylic Substitution Reaction Followed by Cycloisomerization for Synthesis of Polysubstituted Furans 3 from Propargylic Alcohol 1 with 1,3-Dicarbonyl Compounds 2

To a solution of propargylic alcohol 1 and 1,3-dicarbonyl compound 2 in [EMIM][NTf2], 5 mol% of AuBr3 and 15 mol% of AgOTf were added at room temperature. The reaction mixture was stirred at 60 °C (propargylic alcohols 1a for 30 min; propargylic alcohols 1e and 1f for 10 min). After addition of diethyl ether (5 mL) and extraction with diethyl ether (5 mL × 5), the combined organic layers were washed once with brine and dried with Na2SO4. The solvent was removed in vacuo. The residue was purified by column chromatography on silica gel with hexane and AcOEt as eluents to afford polysubstituted furan 3.
1-(5-Benzyl-2-methyl-4-phenylfuran-3-yl)ethan-1-one (3aa): colorless oil, yield = 84%, 32 mg (hexane:AcOEt = 8:1), 1H-NMR (400 MHz, CDCl3) δ 7.41–7.38 (3H, m), 7.29–7.25 (4H, m), 7.24–7.20 (1H, m), 7.14–7.12 (2H, m), 3.81 (2H, s), 2.53 (3H, s), 1.92 (3H, s).
The 1H-NMR is identical with reported values [14].
1-(5-Benzyl-2-ethyl-4-phenylfuran-3-yl)propan-1-one (3ab): colorless oil, yield = 81%, 35 mg (hexane:AcOEt = 8:1), 1H-NMR (400 MHz, CDCl3) δ 7.40–7.37 (3H, m), 7.29–7.25 (4H, m), 7.23–7.20 (1H, m), 7.13–7.11 (2H, m), 3.82 (2H, s), 2.92 (2H, q, J = 7.6 Hz), 2.17 (2H, q, J = 7.2 Hz), 1.25 (3H, t, J = 7.6 Hz), 0.90 (3H, t, J = 7.2 Hz).
The 1H-NMR is identical with reported values [14].
Ethyl 5-benzyl-2-methyl-4-phenylfuran-3-carboxylate (3ac): colorless oil, yield = 48%, 20 mg (hexane:AcOEt = 8:1), 1H-NMR (400 MHz, CDCl3) δ 7.35–7.25 (7H, m), 7.22–7.19 (1H, m), 7.15–7.14 (2H, m), 4.10 (2H, q, J = 7.2 Hz), 3.85 (2H, s), 2.56 (3H, s), 1.07 (3H, t, J = 7.2 Hz).
The 1H-NMR is identical with reported values [14].
Methyl 5-benzyl-2-methyl-4-phenylfuran-3-carboxylate (3ad): colorless oil, yield = 48%, 17 mg (hexane:AcOEt = 8:1), IR (ATR) 3050, 2990, 1712, 1601 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.37–7.25 (7H, m), 7.23–7.20 (1H, m), 7.15–7.14 (2H, m), 3.85 (2H, s), 3.64 (3H, s), 2.56 (3H, s); 13C-NMR (100 MHz, CDCl3) δ 164.6, 158.4, 149.0, 138.2, 132.8, 129.9, 128.5, 128.3, 127.8, 127.1, 126.4, 122.6, 113.4, 51.0, 32.0, 14.3; HRMS (EI) m/z calcd for C20H18O3 306.1256, found 306.1243.
Ethyl 5-benzyl-2,4-diphenylfuran-3-carboxylate (3ae): colorless oil, yield = 39%, 23 mg (hexane:AcOEt = 8:1), 1H-NMR (400 MHz, CDCl3) δ 7.81 (2H, dd, J = 6.6, 1.5 Hz), 7.35–7.25 (7H, m), 7.24–7.21 (1H, m), 7.15–7.13 (2H, m), 4.10 (2H, q, J = 7.2 Hz), 3.85 (2H, s), 2.56 (3H, m), 1.07 (3H, t, J = 7.2 Hz).
The 1H-NMR is identical with reported values [14].
1-(5-Heptyl-2-methyl-4-phenylfuran-3-yl)ethan-1-one (3ca): colorless oil, yield = 35%, 20 mg (hexane:AcOEt = 8:1), 1H-NMR (400 MHz, CDCl3) δ 7.43–7.31 (3H, m), 7.26–7.22 (2H, m), 2.54 (3H, s), 2.45 (2H, t, J = 7.2 Hz), 1.90 (3H, s), 1.56 (2H, br t, J = 7.2 Hz), 1.25–1.18 (8H, m), 0.86 (3H, t, J = 6.9 Hz).
The 1H-NMR is identical with reported values [14].
1-(2,5-Dimethyl-4-phenylfuran-3-yl)ethan-1-one (3ea): colorless oil, yield = 87%, 28 mg (hexane:AcOEt = 8:1), 1H-NMR (400 MHz, CDCl3) δ 7.42–7.34 (3H, m), 7.25–7.23 (2H, m), 2.53 (3H, s), 2.16 (3H, s), 1.93 (3H, s).
The 1H-NMR is identical with reported values [14,45].
1-(2-ethyl-5-menyl-4-pheylfuran-3-yl)propan-1-one (3eb): colorless oil, yield = 81%, 28 mg (hexane:AcOEt = 15:1), IR (ATR) 2980, 2939, 1761, 1697, 1672 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.40–7.33 (3H, m), 7.25–7.22 (2H, m), 2.91 (2H, q, J = 7.6 Hz), 2.18 (3H, s), 2.17 (2H, q, J = 7.2 Hz), 1.27 (3H, t, J = 7.2 Hz), 0.90 (3H, t, J = 7.2 Hz); 13C-NMR (100 MHz, CDCl3) δ 199.6, 160.4, 146.8, 133.9, 129.7, 128.4, 127.2, 121.9, 120.4, 35.8, 21.4, 12.5, 11.6, 8.1; HRMS (EI) m/z calcd for C16H18O2 242.1307, found 242.1296.
Ethyl 2,5-dimethyl-4-phenylfuran-3-carboxylate (3ec): colorless oil, yield = 76%, 26 mg (hexane:AcOEt = 8:1), IR (ATR) 2986, 2938, 1717, 1601 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.35–7.31 (2H, m), 7.29–7.27 (1H, m), 7.24–7.21 (2H, m), 4.09 (2H, q, J = 7.2 Hz), 2.55 (3H, s), 2.18 (3H, s), 1.07 (3H, t, J = 7.2 Hz); 13C-NMR (100 MHz, CDCl3) δ 164.3, 157.4, 147.1, 133.3, 130.0, 127.6, 126.7, 121. 3, 113.5, 59.7, 14.0, 13.9, 11.7; HRMS (EI) m/z calcd for C15H16O3 244.1099, found 244.1095.
Methyl 2,5-dimethyl-4-phenylfuran-3-carboxylate (3ed): colorless oil, yield = 83%, 26 mg (hexane:AcOEt = 8:1), IR (ATR) 2922, 1713, 1602 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.38–7.34 (2H, m), 7.31–7.29 (1H, m), 7.26–7.23 (2H, m), 3.65 (3H, s), 2.57 (3H, s), 2.20 (3H, s); 13C-NMR (100 MHz, CDCl3) δ 164.8, 157.6, 147.2, 133.1, 129.9, 127.7, 126.8, 121.3, 113.2, 50.9, 14.1, 11.8; HRMS (EI) m/z calcd for C14H14O3 230.0943, found 230.0946.
1-[2,5-Dimethyl-4-(naphthalen-1-yl)furan-3-yl]ethan-1-one (3fa): colorless oil, yield = quant., 32 mg (hexane:AcOEt = 8:1), 1H-NMR (400 MHz, CDCl3) δ 7.91–7.87 (2H, m), 7.69–7.67 (1H, m), 7.54–7.42 (3H, m), 7.38 (1H, dd, J = 7.2, 1.2 Hz), 2.64 (3H, s), 2.06 (3H, s), 1.60 (3H, s).
The 1H-NMR is identical with reported values [14].
1-[2-ethyl-5-methyl-4-(naphthalen-1-yl)furan-3-yl]propan-1-one (3fb): colorless oil, yield = 97%, 36 mg (hexane:AcOEt = 8:1), IR (ATR) 3010, 2976, 2937, 1671 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.91–7.87 (2H, m), 7.67 (1H, br t, J = 8.4 Hz), 7.54–7.42 (3H, m), 7.38 (1H, dd, J = 7.2, 1.2 Hz), 3.07 (2H, q, J = 7.2 Hz), 2.08 (3H, s), 2.03–1.97 (1H, m), 1.79–1.73 (1H, m), 1.36 (3H, t, J = 7.6 Hz), 0.68 (3H, t, J = 7.2 Hz); 13C-NMR (100 MHz, CDCl3) δ 199.0, 161.5, 147.7, 133.6, 132.9, 131.6, 128.3, 128.2, 128.1, 126.5, 126.0, 125.6, 125.4, 122.5, 118.0, 34.8, 21.8, 12.3, 11.7, 7.8; HRMS (EI) m/z calcd for C20H20O2 292.1463, found 292.1460.
Ethyl 2,5-dimethyl-4-(naphthalen-1-yl)furan-3-carboxylate (3fc): colorless oil, yield = 83%, 33 mg (hexane:AcOEt = 8:1), 1H-NMR (400 MHz, CDCl3) δ 7.86–7.81 (2H, m), 7.65 (1H, dd, J = 8.0, 0.8 Hz), 7.47–7.36 (3H, m), 7.30 (1H, dd, J = 6.8, 1.2 Hz), 3.78 (2H, q, J = 7.2 Hz), 2.66 (3H, s), 2.11 (3H, s), 0.50 (3H, t, J = 7.2 Hz).
The 1H-NMR is identical with reported values [14].
Methyl 2,5-dimethyl-4-(naphthalen-1-yl)furan-3-carboxylate (3fd): colorless oil, yield = 74%, 24 mg (hexane:AcOEt = 8:1), IR (ATR) 3045, 2994, 2950, 2923, 1716 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.87–7.82 (2H, m), 7.65–7.63 (1H, m), 7.50–7.37 (3H, m), 7.32 (1H, dd, J = 6.8, 1.2 Hz), 3.36 (3H, s), 2.65 (3H, s), 2.07 (3H, m); 13C-NMR (100 MHz, CDCl3) δ 164.6, 157.7, 148.0, 133.4, 132.9, 131.2, 128.1, 127.7, 127.6, 125.8, 125.7, 125.5, 125.1, 119.1, 114.6, 50.8, 14.1, 11.7; HRMS (EI) m/z calcd for C18H16O3 280.1100, found 280.1096.
3-(1,3-Diphenylprop-2-yn-1-yl)pentane-2,4-dione (3′aa) and 4-Acetyl-1,3-diphenylhexene-2,5-dione (3″aa): Propargylic alcohol 1a (79 mg, 0.38 mmol) and acetylacetone (2a) (39 mg, 0.38 mmol) were dissolved in [EMIM][NTf2] (1 mL). AuBr3 (4.2 mg, 0.0096 mmol, 5 mol%) and AgOTf (7.4 mg, 0.029 mmol, 15 mol%) were added at room temperature, and the solution was stirred at room temperature. After the reaction was completed (monitored by thin layer chromatography), the product was extracted from the reaction mixture with diethyl ether (5 mL × 5). The combined organic layers were washed once with brine and dried with Na2SO4. The solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (hexane:AcOEt = 4:1) to afford propargylic substitution product 3′aa (29 mg, 10%) as a colorless oil and hydrated propargylic substitution product 3″aa (98 mg, 83%) as a colorless solid.
3′aa: 1H-NMR (400 MHz, CDCl3) δ 7.41–7.26 (10H, m), 4.67 (1H, d, J = 10.8 Hz), 4.22 (1H, d, J = 10.8 Hz), 2.39 (3H, s), 1.93 (3H, s).
The 1H-NMR is identical with reported values [14,46].
3″aa: Mp. 124–126 °C; IR (ATR) 3030, 29913, 1712, 1697, 1601 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.36–7.30 (3H, m), 7.27–7.21 (2H, m), 7.17–7.15 (2H, m), 6.97–6.95 (2H, m), 4.64 (1H, d, J = 11.2 Hz), 4.60 (1H, d, J = 11.2 Hz), 3.69 (2H, s), 2.24 (3H, s), 1.87 (3H, s); 13C-NMR (100 MHz, CDCl3) δ 205.6, 202.5, 201.5, 134.1, 133.5, 129.6, 129.4, 129.0, 128.4, 128.3, 127.0, 70.6, 57.7, 48.0, 30.9, 30.1; HRMS (EI) m/z calcd for C20H20O3 308.1412, found 308.1417.

3.3. General Procedure for Catalyst Recycling in the Gold-Catalyzed Propargylic Substitution Followed by Cycloisomerization

AuBr3 (5 mol%) and AgOTf (15 mol%) were added to a solution of propargylic alcohol 1f and acetylacetone (2a) in [EMIM][NTf2] (1 mL) at room temperature, and the mixture was stirred at 60 °C. After complete consumption of propargylic alcohol 1f, the product was extracted from the reaction mixture with Et2O (5 mL × 5). The diethyl ether layer was separated. The ionic liquid layer containing the gold catalyst was under reduced pressure for 1 h to remove the ether and water contained and reused for the next reaction.

4. Conclusions

We present an efficient synthesis of polysubstituted furans in ionic liquid via gold-catalyzed propargylic substitution followed by cycloisomerization. This reaction provides an alternative, environmentally friendly method for the synthesis of various polysubstituted furans. We are currently applying it to synthesize biologically important compounds containing furan skeletons. Experimental and theoretical investigations of the reaction mechanism are also in progress.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29225441/s1, 1H, 13C-NMR spectrum.

Author Contributions

Conceptualization, H.C. and N.M.; methodology, H.C. and N.M.; validation, H.C. and N.M.; formal analysis, H.C.; investigation, H.C.; data curation, H.C.; writing—original draft preparation, H.C.; writing—review and editing, Y.H. and N.M.; supervision, N.M.; project administration, N.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Acknowledgments

This work has been partially supported by Nagai Memorial Research Scholarship from the Pharmaceutical Society of Japan (H.C.).

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 29 05441 sch001
Scheme 1. Propargylic substitution followed by cycloisomerization for synthesis of polysubstituted furan.
Scheme 1. Propargylic substitution followed by cycloisomerization for synthesis of polysubstituted furan.
Molecules 29 05441 sch001
Molecules 29 05441 g001
Figure 1. Scope and limitations of gold-catalyzed propargylic substitution of propargylic alcohol 1a with 1,3-dicarbonyl compounds 2a–e followed by cycloisomerization.
Figure 1. Scope and limitations of gold-catalyzed propargylic substitution of propargylic alcohol 1a with 1,3-dicarbonyl compounds 2a–e followed by cycloisomerization.
Molecules 29 05441 g001
Molecules 29 05441 sch002
Scheme 2. The reaction of propargylic alcohol 1b with acetylacetone (2a).
Scheme 2. The reaction of propargylic alcohol 1b with acetylacetone (2a).
Molecules 29 05441 sch002
Molecules 29 05441 sch003
Scheme 3. The reaction of propargylic alcohol 1c with acetylacetone (2a).
Scheme 3. The reaction of propargylic alcohol 1c with acetylacetone (2a).
Molecules 29 05441 sch003
Molecules 29 05441 sch004
Scheme 4. The reaction of propargylic alcohol 1d (R = H) and 1e (R = TMS) with acetylacetone (2a).
Scheme 4. The reaction of propargylic alcohol 1d (R = H) and 1e (R = TMS) with acetylacetone (2a).
Molecules 29 05441 sch004
Molecules 29 05441 g002
Figure 2. Scope and limitations of gold-catalyzed propargylic substitution of propargylic alcohols 1e and 1f with 1,3-dicarbonyl compounds 2a–d followed by cycloisomerization.
Figure 2. Scope and limitations of gold-catalyzed propargylic substitution of propargylic alcohols 1e and 1f with 1,3-dicarbonyl compounds 2a–d followed by cycloisomerization.
Molecules 29 05441 g002
Molecules 29 05441 sch005
Scheme 5. Large-scale preparation of polysubstituted furan 3fa from propargylic alcohol 1f with acetylacetone (2a).
Scheme 5. Large-scale preparation of polysubstituted furan 3fa from propargylic alcohol 1f with acetylacetone (2a).
Molecules 29 05441 sch005
Molecules 29 05441 sch006
Scheme 6. Generation of intermediate 3′aa leading to furan 3aa.
Scheme 6. Generation of intermediate 3′aa leading to furan 3aa.
Molecules 29 05441 sch006
Molecules 29 05441 sch007
Scheme 7. Proposed reaction mechanism of gold-catalyzed propargylic substitution followed by cycloisomerization leading to polysubstituted furan 3aa.
Scheme 7. Proposed reaction mechanism of gold-catalyzed propargylic substitution followed by cycloisomerization leading to polysubstituted furan 3aa.
Molecules 29 05441 sch007
Table 1. Optimization of the reaction conditions for gold-catalyzed propargylic substitution followed by cycloisomerization for the synthesis of polysubstituted furan 3aa.
Table 1. Optimization of the reaction conditions for gold-catalyzed propargylic substitution followed by cycloisomerization for the synthesis of polysubstituted furan 3aa.
Molecules 29 05441 i001
EntryCat. Au (mol%)X eq.Temp.Time3aa Yield
1AuBr3 (5)1r.t.3 days36%
2AuBr3 (5)/AgOTf (15)1r.t.2 days72%
3AuBr3 (5)/AgOTf (15)1100 °C30 min48%
4AuBr3 (5)/AgOTf (15)160 °C30 min84%
5AuBr3 (5)/AgOTf (15)360 °C30 h71%
6AuCl (5)1r.t.3 days30%
7AuCl (5)/AgOTf (5)1r.t.3 days46%
Table 2. Effect of the counter anion of the silver catalyst.
Table 2. Effect of the counter anion of the silver catalyst.
Molecules 29 05441 i002
EntryCatalystsTime3aa Yield
1AuBr3 (5)/AgOTf (15)30 min84%
2AuBr3 (5)/AgNTf2 (15)1 day57%
3AuBr3 (5)/AgBF4 (15)2 days47%
4AuBr3 (5)/AgSbF6 (15)2 daysn.d.
Table 3. Solvent effect in gold-catalyzed propargylic substitution followed by cycloisomerization.
Table 3. Solvent effect in gold-catalyzed propargylic substitution followed by cycloisomerization.
Molecules 29 05441 i003
EntrySolventTemp. (Time)3aa Yield
1[EMIM][NTf2]60 °C (30 min)84%
2[EMIM][CH3CO2]r.t. (1 h) to 100 °C (1 day)no reaction
3[EMIM][Me2PO4] r.t. (1 h) to 100 °C (1 day)no reaction
4[EMIM][HSO4] r.t. (1 h) to 100 °C (1 day)trace
5[EMIM][MeSO4]r.t. (1 h) to 100 °C (1 day)trace
6[EMIM][OTf]r.t. (1 h) to 100 °C (1 day)trace
7ClCH2CH2Cl60 °C (3 h)49%
Table 4. Catalyst recycling in the gold-catalyzed propargylic substitution of propargylic alcohol 1f with acetylacetone (2a) followed by cycloisomerization.
Table 4. Catalyst recycling in the gold-catalyzed propargylic substitution of propargylic alcohol 1f with acetylacetone (2a) followed by cycloisomerization.
Molecules 29 05441 i004
RunTime3fa Yield
110 minQuant.
23 h90%
317 h89%
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Chiaki, H.; Hashimoto, Y.; Morita, N. Gold-Catalyzed Propargylic Substitution Followed by Cycloisomerization in Ionic Liquid: Environmentally Friendly Synthesis of Polysubstituted Furans from Propargylic Alcohols and 1,3-Dicarbonyl Compounds. Molecules 2024, 29, 5441. https://doi.org/10.3390/molecules29225441

AMA Style

Chiaki H, Hashimoto Y, Morita N. Gold-Catalyzed Propargylic Substitution Followed by Cycloisomerization in Ionic Liquid: Environmentally Friendly Synthesis of Polysubstituted Furans from Propargylic Alcohols and 1,3-Dicarbonyl Compounds. Molecules. 2024; 29(22):5441. https://doi.org/10.3390/molecules29225441

Chicago/Turabian Style

Chiaki, Hitomi, Yoshimitsu Hashimoto, and Nobuyoshi Morita. 2024. "Gold-Catalyzed Propargylic Substitution Followed by Cycloisomerization in Ionic Liquid: Environmentally Friendly Synthesis of Polysubstituted Furans from Propargylic Alcohols and 1,3-Dicarbonyl Compounds" Molecules 29, no. 22: 5441. https://doi.org/10.3390/molecules29225441

APA Style

Chiaki, H., Hashimoto, Y., & Morita, N. (2024). Gold-Catalyzed Propargylic Substitution Followed by Cycloisomerization in Ionic Liquid: Environmentally Friendly Synthesis of Polysubstituted Furans from Propargylic Alcohols and 1,3-Dicarbonyl Compounds. Molecules, 29(22), 5441. https://doi.org/10.3390/molecules29225441

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