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Article

Gold(III)-Catalyzed Propargylic Substitution Reaction Followed by Cycloisomerization for Synthesis of Poly-Substituted Furans from N-Tosylpropargyl Amines with 1,3-Dicarbonyl Compounds

by
Nobuyoshi Morita
1,*,
Shingo Uchida
1,
Hitomi Chiaki
1,
Naho Ishii
1,
Kentaro Tanikawa
1,
Kosaku Tanaka III
1,2,
Yoshimitsu Hashimoto
1 and
Osamu Tamura
1,*
1
Department of Pharmacy, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida 194-8543, Japan
2
Research Foundation ITSUU Laboratory, C1232 Kanagawa Science Park R & D Building, 3-2-1 Sakado Takatsu-ku, Kawasaki 213-0012, Japan
*
Authors to whom correspondence should be addressed.
Molecules 2024, 29(2), 378; https://doi.org/10.3390/molecules29020378
Submission received: 30 November 2023 / Revised: 22 December 2023 / Accepted: 3 January 2024 / Published: 11 January 2024
(This article belongs to the Section Organic Chemistry)
Browse Figures
Versions Notes

Abstract

:
The treatment of N-tosylpropargyl amines 1 with 1,3-dicarbonyl compounds 2 in the presence of AuBr3 (5 mol%) and AgOTf (15 mol%) afforded poly-substituted furans 3 in good-to-high yields via the gold-catalyzed cleavage of the sp3 carbon–nitrogen bond.

1. Introduction

Poly-substituted furans are valuable structural motifs in both naturally occurring and artificial compounds with a range of biological activities [1,2,3] and are also used as building blocks to synthesize organic compounds [4,5]. Among the numerous procedures reported for the construction of poly-substituted furans [6,7], the tandem reaction of propargyl alcohols, ethers, or acetoxy with active methylene compounds to produce poly-substituted furans via propargylic substitution followed by cycloisomerization has attracted much attention (Scheme 1, route a) [8,9,10]. In the initial propargylic substitution reaction, a hydroxyl, ether, or acetoxy group in the propargylic derivative serves as a leaving group and the reaction proceeds smoothly via the cleavage of the C-O bond to afford propargylic substitution products, which undergo cycloisomerization to yield furans. However, there are few examples of substitution reactions with nucleophiles using nitrogen leaving groups via C-N bond cleavage [11,12,13,14,15,16,17,18,19,20,21], and even fewer examples of propargylic substitution reactions of propargylic amines with active methylene compounds to obtain poly-substituted furans (Scheme 1, route b) [22]. The reason why there are few examples of reactions via C-N bond cleavage is presumably that nitrogen functional groups have inherently low leaving ability, and in addition, the preparation of nitrogen functional groups from other functional groups is cumbersome. However, given the rapid development of organic and biomolecular chemistry in recent years [23], the development of reactions involving C-N bond cleavage is attracting more attention. For example, Tian and co-workers reported the synthesis of poly-substituted furans from N-tosylpropargyl amine and active methylene compounds [22]. However, their method requires a high loading of ZnCl2 (10 mol%) and TMSCl (50 mol%) and has a narrow scope, with only four examples of the construction of furans reported. Therefore, the development of synthetic methods for the synthesis of poly-substituted furans with cleavage of C-N bonds is a very important topic.
We considered that poly-substituted furans might be synthesized with a propargylic substitution reaction using the NHTs group of N-tosylpropargyl amine as a leaving group [11,12,13,14,15,16,17,18,19,20,21,22], followed by cycloisomerization, based on the strategic use of a gold catalyst (Scheme 2). Investigating the reported examples of substitution reactions using nitrogen leaving groups, it was predicted that nitrogen functional groups bearing the tosyl group as a protecting group would have sufficient leaving ability [11,12,13,14,15,16,17,18,19,20,21]. Gold catalysts are expected to promote propargylic substitution reactions by coordinating with the nitrogen atom of the NHTs group and the triple bond in propargyl amine, giving the propargylic substituted product as an intermediate, followed by cycloisomerization mediated by coordination of the gold catalyst with the triple bond to afford poly-substituted furans. The key point is how efficiently the first- and second-step reactions can be carried out with the same gold catalyst. Here, we report a gold-catalyzed propargylic substitution reaction followed by cycloisomerization for the synthesis of poly-substituted furans from N-tosylpropargyl amines with active methylene compounds.

2. Results

Based on our previous work on the formation of cyclic compounds [24,25,26,27,28,29], we started our study by examining the reaction of N-tosylpropargyl amine 1a as a model substrate with acetylacetone (2a) as a nucleophile in the presence of various gold catalysts and silver catalysts in ClCH2CH2Cl (Table 1).
Treatment of N-tosylpropargyl amine 1a with one equivalent of acetylacetone (2a) in the presence of gold(III) catalyst (5 mol% AuBr3) at reflux afforded the desired product 3aa in a 23% yield (entry 1). Increasing the amount of acetylacetone (2a) to three equivalents in the reaction slightly improved the yield of the desired product 3aa (entry 2). The use of 10 equivalents of acetylacetone (2a) in the reaction gave a complicated mixture (entry 3). The combined system of a gold(III) catalyst (5 mol% AuBr3) and silver catalyst (15 mol% AgOTf) increased the yield of the desired product 3aa (entry 4). Furthermore, extending the reaction time and increasing the equivalent of acetylacetone (2a) improved the yield of the desired product 3aa (entries 5 and 6). In contrast, the reaction with gold(I) catalyst (5 mol% of AuCl/5 mol% AuCl with 15 mol% AgOTf) afforded the product 3aa in low yields (entries 7 and 8). The use of a gold(I) catalyst including phosphine ligand Ph3PAuCl (5 mol%) in the reaction afforded a trace amount of the desired product 3aa (entry 9), whereas cationic gold species generated from Ph3PAuCl (5 mol%) and AgOTf (5 mol%) gave the desired product 3aa in a 25% yield (entry 10). The use of a gold(I) catalyst containing carbene ligand, choloro [1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene]gold(I) (5 mol%: NHCAuCl) in the reaction furnished a trace amount of the product 3aa (entry 11), whereas employing NHCAuCl (5 mol%) and AgOTf (5 mol%) in the reaction afforded the product 3aa in a low yield (entry 12). These results indicate that 5 mol% AuBr3 and 15 mol% AgOTf are a good catalyst system and that the NHTs groups in N-tosylpropargyl amine 1a have sufficient leaving ability in a propargylic substitution reaction.
To examine the effect of the counter anion of the silver co-catalyst, we conducted reactions with various types of silver catalysts, such as AgNTf2, AgSbF6, AgBF4, and AgPF6 (Table 2). Treatment of N-tosylpropargyl amine 1a with three equivalents of acetylacetone (2a) in the presence of AuBr3 (5 mol%) with AgNTf2 (15 mol%) or AgSbF6 (15 mol%) in ClCH2CH2Cl at 60 °C for 19 h afforded the desired product 3aa in moderate yields, 46% or 43%, respectively (entries 2 and 3). The use of AgBF4 (15 mol%) in the reaction furnished the desired product 3aa in a low yield, 24% (entry 4). Employing AgPF6 (15 mol%) in the reaction gave no desired product 3aa (entry 5). These experiments showed that the triflate anion (TfO¯) is effective as a counter anion in the sequential reaction. It has been reported by other groups that the triflate anion (TfO¯) has a good effect as a counter anion in gold-catalyzed reactions [30,31,32].
Next, we examined the effect of solvents such as MeNO2, toluene, CF3CH2OH, and CH3CN (Table 3). The use of MeNO2 in the reaction afforded the desired product 3aa in a moderate yield, 43% (entry 2). The reaction with toluene or CF3CH2OH gave only a low yield of the product 3aa, 33% or 24%, respectively (entries 3 and 4). The use of CH3CN in the reaction gave a complex mixture (entry 5). These experiments showed that dichloroethane (ClCH2CH2Cl) is an effective solvent in the propargylic substitution reaction/cycloisomerization sequences from N-tosylpropargyl amine 1a with acetylacetone (2a).
Finally, the optimal reaction conditions for preparation of the desired product 3aa from N-tosylpropargyl amine 1a with acetylacetone (2a) were found to be 5 mol% AuBr3 and 15 mol% AgOTf in dichloroethane solvent, stirred at 60 °C for 19 h.
We next investigated the scope and limitations of the gold(III)-catalyzed propargylic substitution reaction followed by cycloisomerization for the synthesis of poly-substituted furans 3 from the N-tosylpropargyl amines 1a and 1b and various 1,3-dicarbonyl compounds 2a–g (Table 4). The reaction of the N-tosylpropargylic amines 1a and 2b–g gave the corresponding poly-substituted furans 3ab–ad in good-to-high yields, but the corresponding products 3ae–3ag were obtained in moderate yields. Furthermore, the reaction also proceeds with acetylene bearing a phenyl or even a n-hexyl group at the terminus, with slightly lower yields in the case of the n-hexyl group. It is noteworthy that the reaction of β-keto esters 2c and 2g also afforded poly-substituted furans 3 in satisfactory yields. Poly-substituted furans 3aa (Table 1) and 3ac (Table 4) were also synthesized by the Tian group [22]. Their reaction conditions were a high loading of ZnCl2 (10 mol%) and TMSCl (50 mol%) as reagents in a ClCH2CH2Cl solvent at 70 °C for a 24 h reaction time. Comparing the yields of the poly-substituted furans 3aa and 3ac obtained by our procedure and their procedure, our procedure showed higher yields (3aa: 81% vs. 65%/3ac: 73% vs. 47%).
Next, we investigated the reaction of N-tosylpropargyl amine 1c with no substituent at the terminus of acetylene (Scheme 3). The corresponding product 3da was obtained only in a low yield. On the other hand, when the reaction was carried out with a silyl group-substituted acetylene 1d instead of no substituted acetylene 1c, the product 3da was obtained in a high yield while undergoing desilylation (Scheme 3). Furthermore, it was found that the reaction was faster for substrates with silyl groups than for those with alkyl or aryl groups. This is presumably due to the β-cation-stabilizing effect of the silyl groups [33,34], which would accelerate the cycloisomerization (see Scheme 7).
We next examined the scope and limitations of the reaction with N-tosylpropargyl amines 1d bearing a silyl group at the terminus of acetylene with 1,3-dicarbonyl compounds 2a and 2d (Table 5). The reaction proceeded smoothly to afford desilylated products 3da and 3dd in 89% and 72% yields, respectively. In addition, the reaction of N-tosylpropargyl amine 1e bearing a 1-naphthyl group at the propargylic position with various 1,3-dicarbonyl compounds 2 was investigated (Table 5). The reaction of N-tosylpropargyl amine 1e with 1,3-dicarbonyl compounds 2a and 2c afforded the corresponding furans 3ea and 3ec in good-to-high yields (95% and 74%), but the reaction of 1e with 1,3-dicarbonyl compound 2d furnished only a low yield of furan 3ea.
We next conducted a gram-scale preparation of poly-substituted furan 3da from 2.0 g (5.6 mmol) of N-tosylpropargyl amine 1d and 1.9 g of acetylacetone (2a) in the presence of 5 mol% AuBr3 and 15 mol% AgOTf in ClCH2CH2Cl for 10 h at 60 °C, obtaining the product 3da in an 80% yield (Scheme 4).
The reaction of N-tosylpropargyl amine 1f bearing a methyl group at the propargylic position instead of an aryl group afforded neither the propargylic substitution product 3fa nor the desired product 3aa (Scheme 5), which shows that stabilization of the cation at the propargylic position by the aryl group (phenyl or 1-naphthyl) in N-tosylpropargyl amine 1 is very important for the step of propargylic substitution reaction (see Scheme 7).
To confirm the reaction pathway, the reaction of N-tosylpropargyl amine 1a and acetylacetone (2a) was conducted in the presence of 5 mol% of AuCl in ClCH2CH2Cl at room temperature for 3 h, affording the propargylic substitution product 3′aa in a 38% yield (Scheme 6). Moreover, 3′aa was smoothly converted into the corresponding poly-substituted furan 3aa in an excellent yield in the presence of 5 mol% of AuBr3 and 15 mol% AgOTf at 60 °C in ClCH2CH2Cl. These experiments clearly indicated that the reaction proceeds via a propargylic substitution reaction [34].
A plausible mechanism of the gold(III)-catalyzed propargylic substitution reaction followed by cycloisomerization leading to poly-substituted furan 3aa is shown in Scheme 7. We considered two possible pathways for the propargylic substitution reaction of N-tosylpropargyl amine 1a with acetylacetone (2a). First, the gold catalyst would coordinate with the triple bond and the nitrogen atom in 1a, to promote the propargylic substitution reaction of acetylacetone (2a) (Scheme 7, path a). Second, the propargylic substitution reaction of the gold enolate species A [35,36,37,38,39,40,41,42,43] generated by the reaction of the gold(III) catalyst and acetylacetone (2a) would occur via coordination of the triple bond and the nitrogen atom of 1a (Scheme 7, path b), although it still remains unclear whether the gold(III)-enolate species A is generated in this gold-catalyzed reaction. After completion of the propargylic substitution reaction, the gold catalyst would coordinate to the triple bond of 3′aa to enable smooth cyclization, affording the vinyl gold complex B. Deauration and isomerization would afford the furan 3aa (B→C→3aa). When the substituent on the triple bond of N-tosylpropargyl amines 1 is a silyl group, the reaction would be accelerated by the β-cation-stabilizing effect D of the silyl group [33,34]. This may explain why the reaction of N-tosylpropargyl amines 1d and 1e bearing a silyl group proceeds faster than that of N-tosylpropargyl amines 1 with alkyl or aryl substituents on the triple bond.

3. Materials and Methods

3.1. General Information

1H and 13C NMR spectra were recorded with a JEOL JNM-AL300 (Japan Electron Optics Laboratory Co., Ltd., Tokyo, Japan) or BRUKER AV-300 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 (IR) spectra were recorded with a Shimadzu FTIR-8200A spectrometer (Shimadzu Corporation, Kyoto, Japan). 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 Poly-Substituted Furans 3 from N-Tosylpropargyl Amines 1 with 1,3-Dicarbonyl Compounds 2

Five mol% AuBr3 and fifteen mol% AgOTf were added at room temperature to a solution of N-tosylpropargyl amine 1 and 1,3-dicarbonyl compound 2 in ClCH2CH2Cl, and the mixture was stirred at 60 °C. After the complete consumption of N-tosylpropargyl amine 1 (the reaction was monitored by thin-layer chromatography; usually within 19 h for N-tosylpropargyl amines 1a and 1b, and within 10 h for N-tosylpropargyl amines 1d and 1e), the solvent was removed in vacuo and the crude product was subjected to SiO2 column chromatography (eluents = hexane:AcOEt or diethyl ether) to give poly-substituted furan 3.
1-(5-Benzyl-2-methyl-4-phenylfuran-3-yl)ethan-1-one (3aa); colorless oil, yield = 81%, 33 mg (hexane:AcOEt = 10:1), IR (KBr) 3030, 1672, 1558 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.41–7.36 (4H, m), 7.29–7.23 (4H, m), 7.14–7.12 (2H, m), 3.81 (2H, s), 2.53 (3H, s), 1.92 (3H, s); 13C-NMR (75 MHz, CDCl3) δ 196.0, 157.2, 148.8, 138.1, 133.4, 130.0, 128.5, 128.3, 127.6, 126.4, 122.9, 121.9, 32.0, 30.7, 14.4 (overlapped); HRMS (EI) m/z calcd for C20H18O2 290.1307, found 290.1311.
1-(5-Benzyl-2-ethyl-4-phenylfuran-3-yl)propan-1-one (3ab); colorless oil, yield = 70%, 31 mg (hexane:diethyl ether = 10:1), IR (KBr) 3030, 1672, 1558 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.43–7.35 (4H, m), 7.33–7.24 (4H, m), 7.14–7.11 (2H, m), 3.82 (2H, s), 2.91 (2H, q, J = 7.2 Hz), 2.16 (2H, q, J = 7.5 Hz), 1.25 (3H, t, J = 7.5 Hz), 0.90 (3H, t, J = 7.2 Hz); 13C-NMR (75 MHz, CDCl3) δ 199.4, 161.4, 148.6, 138.2, 133.6, 129.9, 128.5, 128.3, 127.5, 127.2, 126.4, 121.9, 121.5, 35.8, 32.0, 21.5, 12.4, 8.0; HRMS (EI) m/z calcd for C22H22O2 318.1620, found 318.1620.
Ethyl 5-benzyl-2-methyl-4-phenylfuran-3-carboxylate (3ac); colorless oil, yield = 73%, 31 mg (hexane:diethyl ether = 10:1), IR (KBr) 2990, 1708, 1602 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.38–7.32 (4H, m), 7.30–7.22 (4H, m), 7.15–7.12 (2H, m), 4.10 (2H, q, J = 6.9 Hz), 3.85 (2H, s), 2.56 (3H, s), 1.08 (3H, t, J = 6.9 Hz); 13C-NMR (75 MHz, CDCl3) δ 164.2, 158.3, 148.8, 138.3, 133.0, 130.0, 128.5, 128.4, 127.7, 127.0, 126.4, 122.7, 113.6, 59.8, 32.0, 14.2, 13.9; HRMS (EI) m/z calcd for C21H20O3 320.1412, found 320.1417.
The 1H-NMR and 13C-NMR data are identical to the reported values [22].
Ethyl 5-benzyl-2,4-diphenylfuran-3-carboxylate (3ad); colorless oil, yield = 81%, 57 mg (hexane:diethyl AcOEt = 30:1), IR (KBr) 1718 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.81 (2H, dd, J = 6.6, 1.5 Hz), 7.59–7.33 (5H, m), 7.28–7.26 (4H, m), 7.25–7.19 (4H, m), 4.08 (2H, q, J = 6.9 Hz), 3.98 (2H, s), 0.97 (3H, t, J = 6.9 Hz); 13C-NMR (75 MHz, CDCl3) δ 164.5, 156.5, 154.7, 150.0, 138.0, 132.7, 130.0, 129.7, 129.0, 128.9, 128.6, 128.4, 128.1, 128.0, 127.7, 127.3, 126.5, 60.5, 32.3, 13.6; HRMS (EI) m/z calcd for C26H22O3 382.1569, found 382.1570.
Methyl 5-benzyl-4-phenyl-2-propylfuran-3-carboxylate (3ae); colorless oil, yield = 53%, 25 mg (hexane:AcOEt = 20:1), IR (KBr) 3030, 1724 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.37–7.33 (4H, m), 7.30–7.20 (4H, m), 7.14–7.10 (2H, m), 3.86 (2H, s), 3.64 (3H, s), 2.94 (2H, t, J = 7.5 Hz), 1.71 (2H, m), 0.96 (3H, t, J = 7.2 Hz); 13C-NMR (75 MHz, CDCl3) δ 164.7, 162.2, 148.9, 138.3, 133.0, 129.9, 128.5, 128.3, 127.8, 127.0, 126.4, 122.5, 113.0, 50.9, 32.0, 29.9, 21.6, 13.8; HRMS (EI) m/z calcd for C22H22O3 334.1569, found 334.1566.
Methyl 5-benzyl-2-butyl-4-phenylfuran-3-carboxylate (3af); colorless oil, yield = 55%, 27 mg (hexane:AcOEt = 20:1), IR (KBr) 3030, 1714 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.39–7.32 (4H, m), 7.30–7.21 (4H, m), 7.18–7.11 (2H, m), 3.86 (2H, s), 3.63 (3H, s), 2.96 (2H, t, J = 7.2 Hz), 1.71–1.59 (2H, m), 1.43–1.30 (2H, m), 0.92 (3H, t, J = 7.5 Hz); 13C-NMR (75 MHz, CDCl3) δ 164.7, 162.4, 148.9, 138.3, 132.9, 129.9, 128.5, 128.3, 127.7, 127.0, 126.3, 122.5, 112.9, 50.9, 32.0, 30.2, 28.0, 22.3, 13.8; HRMS (EI) m/z calcd for C23H24O3 348.1725, found 348.1723.
Methyl 2,5-dibenzyl-4-phenylfuran-3-carboxylate (3ag); colorless oil, yield = 42%, 23 mg (hexane:AcOEt = 20:1), IR (KBr) 2923, 1710 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.38–7.09 (13H, m), 7.16–7.10 (2H, m), 4.32 (2H, s), 3.85 (2H, s), 3.65, (3H, s); 13C-NMR (75 MHz, CDCl3) δ 164.4, 159.5, 149.8, 137.6, 132.7, 130.0, 128.8, 128.52, 128.47, 128.40, 128.3, 127.8, 127.1, 126.5, 126.4, 126.3, 122.7, 51.0, 33.9, 32.0; HRMS (EI) m/z calcd for C26H22O3 382.1569, found 382.1571.
1-(5-Heptyl-2-methyl-4-phenylfuran-3-yl)ethan-1-one (3ba); colorless oil, yield = 66%, 19 mg (hexane:AcOEt = 20:1), IR (KBr) 2956, 1676 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.43–7.33 (3H, m), 7.25–7.22 (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), 1.25–1.21 (8H, m), 0.86 (3H, t, J = 6.9 Hz); 13C-NMR (75 MHz, CDCl3) δ 196.2, 156.3, 151.1, 133.8, 130.0, 128.4, 127.3, 122.9, 120.6, 31.7, 30.7, 29.0, 28.9, 28.5, 25.7, 22.6, 14.3, 14.0; HRMS (EI) m/z calcd for C20H26O2 298.1933, found 298.1933.
1-(2-Ethyl-5-heptyl-4-phenylfuran-3-yl)propan-1-one (3bb); colorless oil, yield = 61%, 22 mg (hexane:AcOEt = 20:1), IR (KBr) 2956, 1697 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.42–7.33 (3H, m), 7.26–7.21 (2H, m), 2.92 (2H, q, J = 7.5 Hz), 2.46 (2H, t, J = 7.5 Hz), 2.14 (2H, t, J = 7.2 Hz), 1.60–1.55 (2H, m), 1.27 (3H, t, J = 7.2 Hz), 1.29–1.20 (8H, m), 0.89 (3H, t, J = 7.2 Hz), 0.86 (3H, t, J = 6.9 Hz); 13C-NMR (75 MHz, CDCl3) δ 199.7, 160.6, 151.1, 134.1, 129.9, 128.4, 127.3, 121.8, 120.2, 35.8, 31.7, 29.0, 28.9, 28.5, 25.8, 22.6, 21.5, 14.1, 12.4, 8.1; HRMS (EI) m/z calcd for C22H30O2 326.2246, found 326.2236.
Ethyl 5-heptyl-2-methyl-4-phenylfuran-3-carboxylate (3bc); colorless oil, yield = 53%, 19 mg (hexane:AcOEt = 20:1), IR (KBr) 2956, 1708 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.37–7.30 (3H, m), 7.24–7.21 (2H, m), 4.09 (2H, q, J = 6.9 Hz), 2.58 (3H, s), 2.59 (2H, t, J = 7.5 Hz), 1.57–1.53 (2H, m), 1.26–1.20 (8H, m), 1.07 (3H, t, J = 7.2 Hz), 0.86 (3H, t, J = 6.9 Hz); 13C-NMR (75 MHz, CDCl3) δ 164.4, 157.4, 151.3, 133.4, 130.0, 127.5, 126.7, 121.2, 113.5, 59.7, 31.7, 29.0, 28.9, 28.5, 25.8, 22.6, 14.1, 14.0, 13.9; HRMS (EI) m/z calcd for C21H28O3 328.2038, found 328.2030.
Ethyl 5-heptyl-2,4-diphenylfuran-3-carboxylate (3bd); colorless oil, yield = 75%, 36 mg (hexane:AcOEt = 20:1), IR (KBr) 2955, 1718 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.86–7.83 (2H, m), 7.45–7.27 (8H, m), 4.09 (2H, q, J = 6.9 Hz), 2.62 (2H, t, J = 7.5 Hz), 1.68–1.62 (2H, m), 1.26–1.20 (8H, m), 0.97 (3H, t, J = 6.9 Hz), 0.86 (3H, t, J = 6.9 Hz); 13C-NMR (75 MHz, CDCl3) δ 164.7, 153.9, 152.5, 133.1, 130.2, 129.7, 128.7, 128.1, 127.9, 127.6, 127.0, 122.8, 114.7, 60.4, 31.7, 29.1, 28.9, 28.4, 26.0, 22.6, 14.1, 13.6; HRMS (EI) m/z calcd for C26H30O3 390.2195, found 390.2189.
Methyl 5-heptyl-4-phenyl-2-propylfuran-3-carboxylate (3be); colorless oil, yield = 33%, 15 mg (hexane:AcOEt = 20:1), IR (KBr) 2957, 1732 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.38–7.26 (3H, m), 7.25–7.21 (2H, m), 3.62 (3H, s), 2.95 (2H, t, J = 7.2 Hz), 2.50 (2H, t, J = 7.2 Hz), 1.77–1.70 (2H, m), 1.58–1.54 (2H, m), 1.25–1.19 (8H, m), 0.99 (3H, t, J = 7.2 Hz), 0.86 (3H, t, J = 6.9 Hz); 13C-NMR (75 MHz, CDCl3) δ 164.9, 161.4, 151.4, 133.4, 129.9, 127.6, 126.7, 121.0, 112.8, 50.8, 31.7, 29.9, 29.0, 28.9, 28.4, 25.8, 22.6, 21.6, 14.1, 13.8; HRMS (EI) m/z calcd for C22H30O3 342.2195, found 342.2195.
1-(2,5-Dimethyl-4-phenylfuran-3-yl)ethan-1-one (3da); colorless oil, yield = 89%, 27 mg (hexane:AcOEt = 10:1), 1H-NMR (300 MHz, CDCl3) δ 7.40–7.34 (3H, m), 7.26–7.23 (2H, m), 2.53 (3H, s), 2.16 (3H, s), 1.93 (3H, s); 13C-NMR (75 MHz, CDCl3) δ 196.2, 156.2, 146.9, 133.7, 129.9, 128.4, 127.3, 123.0, 120.8, 30.7, 14.2, 11.6.
The 1H-NMR and 13C-NMR data are identical to the reported values [44].
Ethyl 2,5-dimethyl-4-phenylfuran-3-carboxylate (3dd); colorless oil, yield = 72%, 25 mg (hexane:AcOEt = 10:1), 1H-NMR (300 MHz, CDCl3) δ 7.38–7.23 (4H, m), 4.12 (2H, q, J = 7.2 Hz), 2.57 (3H, s), 2.20 (3H, s), 1.09 (3H, t, J = 7.2 Hz); 13C-NMR (75 MHz, CDCl3) δ 164.3, 157.4, 147.1, 133.3, 130.0, 127.6, 126.7, 121.3, 113.5, 59.7, 14.1, 13.9, 11.7.
The 1H-NMR and 13C-NMR data are identical to the reported values [9].
1-[2,5-Dimethyl-4-(naphthalen-1-yl)furan-3-yl]ethan-1-one (3ea); colorless oil, yield = 95%, 31 mg (hexane:AcOEt = 15:1), IR (KBr) 1671, 1560, 1507, 1308 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.92–7.87 (2H, m), 7.69 (1H, dd, J = 8.1, 0.9 Hz), 7.55–7.41 (3H, m), 7.38 (1H, dd, J = 7.2, 1.5 Hz), 2.64 (3H, s), 2.06 (3H, s), 1.58 (3H, s); 13C-NMR (75 MHz, CDCl3) δ 195.9, 157.1. 147.8, 133.7, 133.0, 131.4, 128.4, 128.38, 128.27, 128.22, 126.6, 126.1, 125.6, 125.5, 118.4, 29.9, 14.6, 11.7; HRMS (EI) m/z calcd for C18H16O2 264.1150, found 264.1153.
Ethyl 2,5-dimethyl-4-(naphthalen-1-yl)furan-3-carboxylate (3ec); colorless oil, yield = 74%, 27 mg (hexane:AcOEt = 20:1), IR (KBr) 1707, 1596, 1310 1201, 1085 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.87–7.81 (2H, m), 7.67–7.64 (1H, m), 7.50–7.35 (3H, m), 7.30 (1H, dd, J = 7.2, 1.5 Hz), 3.76 (2H, q, J = 7.2 Hz), 2.66 (3H, s), 2.11 (3H, s), 0.50 (3H, t, J = 7.2 Hz); 13C-NMR (75 MHz, CDCl3) δ 164.2, 157.7, 147.8, 133.4, 133.2, 131.6, 128.0, 127.6, 126.0, 125.6, 125.5, 125.1, 119.1, 114.9, 59.4, 14.0, 13.1, 11.7 (overlapped); HRMS (EI) m/z calcd for C19H18O3 294.1256, found 294.1255.
Ethyl 5-methyl-4-(naphthalen-1-yl)-2-phenylfuran-3-carboxylate (3ed); colorless oil, yield = 38%, 33 mg (hexane:AcOEt = 20:1), IR (KBr) 1712, 1492, 1374, 1312, 1207, 1112, 1097 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.99–7.95 (2H, m), 7.90–7.84 (2H, m), 7.77–7.74 (1H, m), 7.53–7.67 (7H, m), 3.74 (2H, q, J = 7.2 Hz), 2.23 (3H, s), 0.41 (3H, t, J = 7.2 Hz); 13C-NMR (75 MHz, CDCl3) δ 164.2, 155.0, 149.2, 133.5, 133.1, 131.2, 130.1, 128.9, 128.2, 127.9, 127.7, 127.6, 125.9, 125.8, 125.6, 125.2, 121.2, 115.8, 60.0, 12.9, 12.0 (overlapped); HRMS (EI) m/z calcd for C24H20O3 356.1412, found 356.1411.
3-(1,3-Diphenylprop-2-yn-1-yl)pentane-2,4-dione (3′aa); To a solution of N-tosylpropargyl amine 1a (50 mg, 0.14 mmol) and acetylacetone (2a) (42 mg, 0.42 mmol) in ClCH2CH2Cl (2 mL), AuCl (1.6 mg, 0.0071 mmol, 5 mol%) was added at room temperature. The reaction mixture was stirred at 60 °C for 3 h (the reaction was monitored by thin-layer chromatography). After the complete consumption of N-tosylpropargyl amine 1a, the solvent was removed in vacuo and the crude product was subjected to SiO2 column chromatography (hexane:diethyl ether = 10:1) to give the propargylic substitution product 3′aa (15 mg, 38%) as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 7.50–7.26 (10H, m), 4.67 (1H, d, J = 11.1 Hz), 4.21 (1H, d, J = 11.1 Hz), 2.39 (3H, s), 1.93 (3H, s); 13C-NMR (75 MHz, CDCl3) δ 201.65, 201.60, 138.2, 131.6, 128.9, 128.34, 128.25, 128.1, 127.8, 122.7, 88.0, 84.9, 75.7, 38.1, 31.1, 28.7.
The 1H-NMR and 13C-NMR data are identical to the reported values [45].

4. Conclusions

In conclusion, we present a gold(III)-catalyzed propargylic substitution reaction followed by cycloisomerization for the synthesis of poly-substituted furans 3 from N-tosylpropargyl amines 1 with 1,3-dicarbonyl compounds 2. The reaction proceeds via the propargylic substitution product intermediate 3′aa. We are currently applying this method to the synthesis of biologically active cyclic ether derivatives. Experimental and theoretical investigations on the reaction mechanism are also in progress.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29020378/s1, 1H, 13C-NMR spectrum.

Author Contributions

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

Funding

This work was financially supported by the JSPS KAKENHI (grant number 20 K05517) for N.M.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Gutiérrez, M.; Capson, T.L.; Guzman, H.M.; González, J.; Ortega-Barría, E.; Quiñoá, E.; Riguera, R. Leptolide, a New Furanocembranolide Diterpene from Leptogorgia alba. J. Nat. Prod. 2005, 68, 614–616. [Google Scholar] [CrossRef] [PubMed]
  2. Riley, A.P.; Groer, C.E.; Young, D.; Ewald, A.W.; Kivell, B.M.; Prisinzano, T.E. Synthesis and κ-Opioid Receptor Activity of Furan-Substituted Salvinorin A Analogues. J. Med. Chem. 2014, 57, 10464–10475. [Google Scholar] [CrossRef]
  3. Phillips, M.B.; Sullivan, M.M.; Villalta, P.W.; Peterson, L.A. Covalent Modification of Cytochrome c by Reactive Metabolites of Furan. Chem. Res. Toxicol. 2014, 27, 129–135. [Google Scholar] [CrossRef] [PubMed]
  4. Lipshutz, B.H. Five-Membered Heteroaromatic Rings as Intermediates in Organic Synthesis. Chem. Rev. 1986, 86, 795–819. [Google Scholar] [CrossRef]
  5. Makarov, A.S.; Uchuskin, M.G.; Trushkov, I.V. Furan Oxidation Reactions in the Total Synthesis of Natural Products. Synthesis 2018, 50, 3059–3086. [Google Scholar]
  6. Brown, R.C.D. Developments of Furan Syntheses. Angew. Chem. Int. Ed. 2005, 44, 850–852. [Google Scholar] [CrossRef] [PubMed]
  7. Duc, D.X. Recent Progress in the Synthesis of Furan. Mini-Rev. Org. Chem. 2019, 16, 422–452. [Google Scholar] [CrossRef]
  8. Gluevich, A.V.; Dudnik, A.S.; Chernyak, N.; Gevorgyan, V. Transition Metal-Mediated Synthesis of Monocyclic Aromatic Heterocycles. Chem. Rev. 2013, 113, 3084–3213. [Google Scholar] [CrossRef]
  9. Suhre, M.H.; Reif, M.; Kirsch, S.F. Gold(I)-Catalyzed Synthesis of Highly Substituted Furans. Org. Lett. 2005, 7, 3925–3927. [Google Scholar] [CrossRef]
  10. Hoffmann, M.; Miaskiewicz, S.; Weibel, J.-M.; Pale, P.; Blanc, A. Gold(I)-Catalyzed Formation of Furans from γ-Acyloxyalkynyl Ketones. Beilstein J. Org. Chem. 2013, 9, 1774–1780. [Google Scholar] [CrossRef]
  11. Lee, H.J.; Seong, M.R.; Kim, J.N. Friedel–Crafts Reaction of the Baylis–Hillman Adducts of N-Tosylimine Derivatives. Tetrahedron Lett. 1998, 39, 6223–6226. [Google Scholar] [CrossRef]
  12. Seong, M.R.; Lee, H.J.; Kim, J.N. Decarbonylative Diarylation Reaction of N-Tosylated α-Amino Acids. Tetrahedron Lett. 1998, 39, 6219–6222. [Google Scholar] [CrossRef]
  13. Lee, H.J.; Seong, M.R.; Song, H.N.; Kim, J.N. Friedel–Crafts Reaction of Tosylamide Derivatives: A Useful Source of Carbocationic Species. Bull. Korean Chem. Soc. 1999, 20, 267–268. [Google Scholar]
  14. Esquivias, J.; Arrayás, R.G.; Carretero, J.C. A Copper(II)-Catalyzed Aza-Friedel–Crafts Reaction of N-(2-Pyridyl)sulfonyl Aldimines: Synthesis of Unsymmetrical Diaryl Amines and Triaryl Methanes. Angew. Chem. Int. Ed. 2006, 45, 629–633. [Google Scholar] [CrossRef] [PubMed]
  15. Lee, K.Y.; Lee, H.S.; Kim, H.S.; Kim, J.N. AuCl3-Catalyzed Propargylation of Arenes with N-Tosylpropargyl Amine: Synthesis of 1,3-Diarylpropanes. Bull. Korean Chem. Soc. 2008, 29, 1441–1442. [Google Scholar]
  16. Liu, C.-R.; Li, M.-B.; Yang, C.-F.; Tian, S.-K. Catalytic Selective Bis-arylation of Imines with Anisole, Phenol, Thioanisole and Analogues. Chem. Commun. 2008, 1249–1251. [Google Scholar] [CrossRef] [PubMed]
  17. He, Q.-L.; Sun, F.-L.; Zheng, X.-J.; You, S.-L. Brønsted Acid Catalyzed Synthesis of Unsymmetrical Arylbis(3-indolyl)methanes. Synlett 2009, 1111–1114. [Google Scholar]
  18. Liu, C.-R.; Li, M.-B.; Cheng, D.-J.; Yang, C.-F.; Tian, S.-K. Catalyst-Free Alkylation of Sulfinic Acids with Sulfonamides via sp3 C–N Bond Cleavage at Room Temperature. Org. Lett. 2009, 11, 2543–2545. [Google Scholar] [CrossRef]
  19. Liu, C.-R.; Yang, F.-L.; Jin, Y.-Z.; Ma, X.-T.; Cheng, D.-J.; Li, N.; Tian, S.-K. Catalytic Regioselective Synthesis of Structurally Diverse Indene Derivatives from N-Benzylic Sulfonamides and Disubstituted Alkynes. Org. Lett. 2010, 12, 3832–3835. [Google Scholar] [CrossRef]
  20. Yang, C.-F.; Wang, J.-Y.; Tian, S.-K. Catalytic Decarboxylative Alkylation of β-Keto Acids with Sulfonamides via the Cleavage of Carbon–Nitrogen and Carbon–Carbon Bonds. Chem. Commun. 2011, 47, 8343–8345. [Google Scholar] [CrossRef]
  21. Liu, J.; Wang, L.; Zheng, X.; Wang, A.; Zhu, M.; Yu, J.; Shen, Q. Yb(OTf)3-Promoted Effective Benzylation and Allylation with N-Tosylamino Group as a Stable Leaving Group. Tetrahedron Lett. 2012, 53, 1843–1846. [Google Scholar] [CrossRef]
  22. Liu, C.-R.; Li, M.-B.; Yang, C.-F.; Tian, S.-K. Selective Benzylic and Allylic Alkylation of Protic Nucleophiles with Sulfonamides through Double Lewis Acid Catalyzed Cleavage of sp3 Carbon–Nitrogen Bonds. Chem. Eur. J. 2009, 15, 793–797. [Google Scholar] [CrossRef] [PubMed]
  23. Nichols, D.E.; Nichols, C.D. Serotonin Receptors. Chem. Rev. 2008, 108, 1614–1641. [Google Scholar] [CrossRef]
  24. Morita, N.; Tsunokake, T.; Narikiyo, Y.; Harada, M.; Tachibana, T.; Saito, Y.; Ban, S.; Hashimoto, Y.; Okamoto, I.; Tamura, O. Gold(I)/(III)-Catalyzed Synthesis of 2-Substituted Puperidines; Vallency-Controlled Cyclization Modes. Tetrahedron Lett. 2015, 56, 6269–6272. [Google Scholar] [CrossRef]
  25. Morita, N.; Saito, Y.; Muraji, A.; Ban, S.; Hashimoto, Y.; Okamoto, I.; Tamura, O. Gold-Catalyzed Synthesis of 2-Substituted Azepanes; Strategic Use of Soft Gold(I) and Hard Gold(III) Catalysts. Synlett 2016, 27, 1936–1940. [Google Scholar] [CrossRef]
  26. Morita, N.; Miyamoto, M.; Yoda, A.; Yamamoto, M.; Ban, S.; Hashimoto, Y.; Tamura, O. Gold-Catalyzed Dehydrative Friedel-Crafts Reaction and Nazarov Cyclization Sequence: An Efficient Synthesis of 1,3-Diarylindenes from Propargylic Alcohols. Tetrahedron Lett. 2015, 57, 4460–4463. [Google Scholar] [CrossRef]
  27. Morita, N.; Oguro, K.; Takahashi, S.; Kawahara, M.; Ban, S.; Hashimoto, Y.; Tamura, O. Gold(III)-Catalyzed Synthesis of 2,3,4-Trisubstituted Dihydropyrans from Propargylic Alcohols with 1,3-Dicarbonyl compounds. Heterocycles 2017, 95, 172–180. [Google Scholar]
  28. Morita, N.; Sano, A.; Sone, A.; Aonuma, S.; Matsunaga, A.; Hashimoto, Y.; Tamura, O. Efficient One-Pot Synthesis of Substituted Oxazoles from 3-Trimethylsilylpropargylic Alcohols and Amides by Gold-Catalyzed Substitution followed by Cycloisomerization. Heterocycles 2018, 97, 719–728. [Google Scholar]
  29. Morita, N.; Yasuda, A.; Shibata, M.; Ban, S.; Hashimoto, Y.; Okamoto, I.; Tamura, O. Gold(I)/(III)-Catalyzed Synthesis of Cyclic Ethers; Vallency-Controlled Cyclization Modes. Org. Lett. 2015, 17, 2668–2671. [Google Scholar] [CrossRef]
  30. Biasiolo, L.; Trinchillo, M.; Belanzoni, P.; Belpassi, L.; Brusico, V.; Ciancaleoni, G.; D’Amora, A.; Macchioni, A.; Tarantelli, F.; Zuccaccia, D. Unexpected Anion Effect in the Alkoxylation of Alkynes Catalyzed by N-Heterocyclic Carbene (NHC) Cationic Gold Complexes. Chem. Eur. J. 2014, 20, 14594–14598. [Google Scholar] [CrossRef]
  31. Jia, M.; Bandini, M. Counterion Effects in Homogeneous Gold Catalysis. ACS Catal. 2015, 5, 1638–1652. [Google Scholar] [CrossRef]
  32. Sabatelli, F.; Segato, J.; Belpassi, L.; Del Zotto, A.; Zuccaccia, D.; Belanzoni, P. Monitoring of the Pre-Equilibrium Step in the Alkyne Hydration Reaction Catalyzed by Au(III) Complexes: A Computational Study Based on Experimental Evidences. Molecules 2021, 26, 2445. [Google Scholar] [CrossRef] [PubMed]
  33. Wierschke, S.G.; Chandrasekhar, J.; Jorgensen, W.L. Magnitude and Origin of the β-Silicon Effect on Carbenium Ions. J. Am. Chem. Soc. 1985, 107, 1496–1500. [Google Scholar] [CrossRef]
  34. Kozar, L.G.; Clark, R.D.; Heathcock, C.H. Synthesis of Bicyclo[2.2.2]octenes and Bicyclo[3.2.2]nonenes by π-Cyclization. J. Org. Chem. 1977, 42, 1386–1389. [Google Scholar] [CrossRef]
  35. Dénès, F.; Pérez-Luna, A.; Chemla, F. Addition of Metal Enolate Derivatives to Unactivated Carbon–Carbon Multiple Bonds. Chem. Rev. 2010, 110, 2366–2447. [Google Scholar] [CrossRef]
  36. Rodríguez, A.; Moran, W.J. Furan Synthesis through AuCl3-Catalysed Cycloisomerization of β-Alkynyl β-Ketoesters. Tetrahedron Lett. 2011, 52, 2605–2607. [Google Scholar] [CrossRef]
  37. Murakami, M.; Inouye, M.; Suginome, M.; Ito, Y. Reactions of (Triphenylphosphine)gold(I) Enolates and Homoenolates. Bull. Chem. Soc. Jpn. 1988, 61, 3649–3652. [Google Scholar] [CrossRef]
  38. Yao, X.; Li, C.-J. Highly Efficient Addition of Activated Methylene Compounds to Alkenes Catalyzed by Gold and Silver. J. Am. Chem. Soc. 2004, 126, 6884–6885. [Google Scholar] [CrossRef]
  39. Nguyen, R.-V.; Yao, X.-Q.; Bohle, D.S.; Li, C.-J. Gold- and Silver-Catalyzed Highly Regioselective Addition of Active Methylenes to Dienes, Triene, and Cyclic Enol Ethers. Org. Lett. 2005, 7, 673–675. [Google Scholar] [CrossRef]
  40. Zhou, C.-Y.; Che, C.-M. Highly Efficient Au(I)-Catalyzed Intramolecular Addition of β-Ketoamide to Unactivated Akenes. J. Am. Chem. Soc. 2007, 129, 5828–5829. [Google Scholar]
  41. Wang, Y.-F.; Wang, C.-J.; Feng, Q.-Z.; Zhai, J.-J.; Qi, S.-S.; Zhong, A.-G.; Chu, M.-M.; Xu, D.-Q. Copper-Catalyzed Asymmetric 1,6-Conjugate Addition of in situ Generated para-Quinone Methids with β-Ketoesters. Chem. Commun. 2022, 58, 6653–6656. [Google Scholar] [CrossRef] [PubMed]
  42. Komiya, S.; Kochi, J.K. Reversible Linkage Isomerisms of β-Diketonato Ligands. Oxygen-Bonded and Carbon-Bonded Structures in Gold(III) Acetylacetonate Complexs Induced by Phosphines. J. Am. Chem. Soc. 1977, 99, 3695–3704. [Google Scholar] [CrossRef]
  43. Zharkova, G.I.; Baidina, I.A.; Igumenov, I.K. X-Ray Diffraction Study of Volatile Complexes of Dimethylgold(III) Derived from Symmetrical β-Diketones. J. Struc. Chem. 2006, 47, 1117–1126. [Google Scholar] [CrossRef]
  44. Li, L.; Zhao, M.-N.; Ren, Z.-H.; Li, J.; Guan, Z.-H. Synthesis of Tetrasubstituted NH Pyrroles and Polysubstituted Furans via an Addition and Cyclization Strategy. Synthesis 2012, 44, 532–540. [Google Scholar] [CrossRef]
  45. Masuyama, Y.; Hayashi, M.; Suzuki, N. SnCl2-Catalyzed Propargylic Substitution of Propargylic Alcohols with Carbon and Nitrogen Nucleophiles. Eur. J. Org. Chem. 2013, 2013, 2914–2921. [Google Scholar] [CrossRef]
Molecules 29 00378 sch001
Scheme 1. Tandem reaction for synthesis of poly-substituted furans from propargylic alcohols or propargyl amines with 1,3-dicarbonyl compounds.
Scheme 1. Tandem reaction for synthesis of poly-substituted furans from propargylic alcohols or propargyl amines with 1,3-dicarbonyl compounds.
Molecules 29 00378 sch001
Molecules 29 00378 sch002
Scheme 2. Strategic use of gold catalyst for the synthesis of poly-substituted furans from N-tosylpropargyl amines with 1,3-dicarbonyl compounds.
Scheme 2. Strategic use of gold catalyst for the synthesis of poly-substituted furans from N-tosylpropargyl amines with 1,3-dicarbonyl compounds.
Molecules 29 00378 sch002
Molecules 29 00378 sch003
Scheme 3. The reaction of N-tosylpropargyl amines 1c (R = H) and 1d (R = TMS) with acetylacetone (2a).
Scheme 3. The reaction of N-tosylpropargyl amines 1c (R = H) and 1d (R = TMS) with acetylacetone (2a).
Molecules 29 00378 sch003
Molecules 29 00378 sch004
Scheme 4. Large-scale preparation of poly-substituted furan 3da from N-tosylpropargyl amine 1d with acetylacetone (2a).
Scheme 4. Large-scale preparation of poly-substituted furan 3da from N-tosylpropargyl amine 1d with acetylacetone (2a).
Molecules 29 00378 sch004
Molecules 29 00378 sch005
Scheme 5. The reaction of N-tosylpropargyl amines 1f bearing a methyl group at the propargylic position with acetylacetone (2a).
Scheme 5. The reaction of N-tosylpropargyl amines 1f bearing a methyl group at the propargylic position with acetylacetone (2a).
Molecules 29 00378 sch005
Molecules 29 00378 sch006
Scheme 6. Generation of intermediate 3′aa leading to poly-substituted furan 3aa.
Scheme 6. Generation of intermediate 3′aa leading to poly-substituted furan 3aa.
Molecules 29 00378 sch006
Molecules 29 00378 sch007
Scheme 7. Plausible mechanism of gold(III)-catalyzed propargylic substitution reaction followed by cycloisomerization leading to poly-substituted furan 3aa.
Scheme 7. Plausible mechanism of gold(III)-catalyzed propargylic substitution reaction followed by cycloisomerization leading to poly-substituted furan 3aa.
Molecules 29 00378 sch007
Table 1. Optimization of the reaction conditions for gold(III)-catalyzed propargylic substitution reaction followed by cycloisomerization.
Table 1. Optimization of the reaction conditions for gold(III)-catalyzed propargylic substitution reaction followed by cycloisomerization.
Molecules 29 00378 i001
EntryCat. Au (mol%)x Eq.Temp.Time3aa Yield
1AuBr3 (5)1reflux4 h23%
2AuBr3 (5)3reflux7 h33%
3AuBr3 (5)10reflux7 hcomplex mixture
4AuBr3 (5)/AgOTf (15)160 °C5 h63%
5AuBr3 (5)/AgOTf (15)360 °C10 h71%
6AuBr3 (5)/AgOTf (15)360 °C19 h81%
7AuCl (5)360 °C19 h7%
8AuCl (5)/AgOTf (15)360 °C19 h26%
9Ph3PAuCl (5)360 °C19 htrace
10Ph3PAuCl (5)/AgOTf (5)360 °C19 h25%
11NHCAuCl (5)360 °C19 htrace
12NHCAuCl (5)/AgOTf (5)360 °C19 h22%
Table 2. Effect of the counter anion of silver catalyst in gold(III)-catalyzed propargylic substitution reaction followed by cycloisomerization.
Table 2. Effect of the counter anion of silver catalyst in gold(III)-catalyzed propargylic substitution reaction followed by cycloisomerization.
Molecules 29 00378 i002
EntrySilver CatalystYield
1AgOTf81%
2AgNTf246%
3AgSbF643%
4AgBF424%
5AgPF6no reaction
Table 3. Solvent effect in gold(III)-catalyzed propargylic substitution reaction followed by cycloisomerization.
Table 3. Solvent effect in gold(III)-catalyzed propargylic substitution reaction followed by cycloisomerization.
Molecules 29 00378 i003
EntrySolventYield
1ClCH2CH2Cl81%
2MeNO243%
3Toluene33%
4CF3CH2OH24%
5CH3CNcomplex mixture
Table 4. Scope and limitations of the gold(III)-catalyzed propargylic substitution reaction followed by cycloisomerization of N-tosylpropargyl amines 1a and 1b with 1,3-dicarbonyl compounds 2a–g.
Table 4. Scope and limitations of the gold(III)-catalyzed propargylic substitution reaction followed by cycloisomerization of N-tosylpropargyl amines 1a and 1b with 1,3-dicarbonyl compounds 2a–g.
Molecules 29 00378 i004
Table 5. Scope and limitations of the gold(III)-catalyzed propargylic substitution reaction followed by cycloisomerization of N-tosylpropargyl amines 1d and 1e with 1,3-dicarbonyl compounds 2.
Table 5. Scope and limitations of the gold(III)-catalyzed propargylic substitution reaction followed by cycloisomerization of N-tosylpropargyl amines 1d and 1e with 1,3-dicarbonyl compounds 2.
Molecules 29 00378 i005
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Morita, N.; Uchida, S.; Chiaki, H.; Ishii, N.; Tanikawa, K.; Tanaka, K., III; Hashimoto, Y.; Tamura, O. Gold(III)-Catalyzed Propargylic Substitution Reaction Followed by Cycloisomerization for Synthesis of Poly-Substituted Furans from N-Tosylpropargyl Amines with 1,3-Dicarbonyl Compounds. Molecules 2024, 29, 378. https://doi.org/10.3390/molecules29020378

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Morita N, Uchida S, Chiaki H, Ishii N, Tanikawa K, Tanaka K III, Hashimoto Y, Tamura O. Gold(III)-Catalyzed Propargylic Substitution Reaction Followed by Cycloisomerization for Synthesis of Poly-Substituted Furans from N-Tosylpropargyl Amines with 1,3-Dicarbonyl Compounds. Molecules. 2024; 29(2):378. https://doi.org/10.3390/molecules29020378

Chicago/Turabian Style

Morita, Nobuyoshi, Shingo Uchida, Hitomi Chiaki, Naho Ishii, Kentaro Tanikawa, Kosaku Tanaka, III, Yoshimitsu Hashimoto, and Osamu Tamura. 2024. "Gold(III)-Catalyzed Propargylic Substitution Reaction Followed by Cycloisomerization for Synthesis of Poly-Substituted Furans from N-Tosylpropargyl Amines with 1,3-Dicarbonyl Compounds" Molecules 29, no. 2: 378. https://doi.org/10.3390/molecules29020378

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