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

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.


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 ZnCl 2 (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.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.
with acetylacetone (2a) as a nucleophile in the presence of various gold catalysts and silver catalysts in ClCH 2 CH 2 Cl (Table 1).

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).

Entry
Cat. Au (mol%) x Eq.Temp.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.

Entry
Cat. Au (mol%) x Eq.Temp.Treatment of N-tosylpropargyl amine 1a with one equivalent of acetylacetone (2a) in the presence of gold(III) catalyst (5 mol% AuBr 3 ) 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% AuBr 3 ) 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 Ph 3 PAuCl (5 mol%) in the reaction afforded a trace amount of the desired product 3aa (entry 9), whereas cationic gold species generated from Ph 3 PAuCl (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% AuBr 3 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 AgNTf 2 , AgSbF 6 , AgBF 4 , and AgPF 6 (Table 2).Treatment of N-tosylpropargyl amine 1a with three equivalents of acetylacetone (2a) in the presence of AuBr 3 (5 mol%) with AgNTf 2 (15 mol%) or AgSbF 6 (15 mol%) in ClCH 2 CH 2 Cl 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 AgBF 4 (15 mol%) in the reaction furnished the desired product 3aa in a low yield, 24% (entry 4).Employing AgPF 6 (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].
Table 2. Effect of the counter anion of silver catalyst in gold(III)-catalyzed propargylic substitution reaction followed by cycloisomerization.
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 (TfOˉ) is effective as a counter anion in the sequential reaction.It has been reported by other groups that the triflate anion (TfOˉ) has a good effect as a counter anion in goldcatalyzed reactions [30][31][32].
Table 2. Effect of the counter anion of silver catalyst in gold(III)-catalyzed propargylic substitution reaction followed by cycloisomerization.

Entry
Silver Catalyst Yield 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 hours.Next, we examined the effect of solvents such as MeNO 2 , toluene, CF 3 CH 2 OH, and CH 3 CN (Table 3).The use of MeNO 2 in the reaction afforded the desired product 3aa in a moderate yield, 43% (entry 2).The reaction with toluene or CF 3 CH 2 OH gave only a low yield of the product 3aa, 33% or 24%, respectively (entries 3 and 4).The use of CH 3 CN in the reaction gave a complex mixture (entry 5).These experiments showed that dichloroethane (ClCH 2 CH 2 Cl) is an effective solvent in the propargylic substitution reaction/cycloisomerization sequences from N-tosylpropargyl amine 1a with acetylacetone (2a).
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 (TfOˉ) is effective as a counter anion in the sequential reaction.It has been reported by other groups that the triflate anion (TfOˉ) has a good effect as a counter anion in goldcatalyzed 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 hours.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% AuBr 3 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 ZnCl 2 (10 mol%) and TMSCl (50 mol%) as reagents in a ClCH 2 CH 2 Cl 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%).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 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 1,3dicarbonyl compound 2d furnished only a low yield of furan 3ea.We next conducted a gram-scale preparation 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 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.
Molecules 2024, 29, x FOR PEER REVIEW 6 of 13 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 1,3dicarbonyl 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 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% AuBr 3 and 15 mol% AgOTf in ClCH 2 CH 2 Cl 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).
Scheme 5.The reaction of N-tosylpropargyl amines 1f bearing a methyl group at the propargylic position with acetylacetone (2a).
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 Ntosylpropargyl 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 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).
Molecules 2024, 29, x FOR PEER REVIEW 7 of 13 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).
Scheme 5.The reaction of N-tosylpropargyl amines 1f bearing a methyl group at the propargylic position with acetylacetone (2a).
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 Ntosylpropargyl 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 Scheme 5.The reaction of N-tosylpropargyl amines 1f bearing a methyl group at the propargylic position with acetylacetone (2a).
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 ClCH 2 CH 2 Cl 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 polysubstituted furan 3aa in an excellent yield in the presence of 5 mol% of AuBr 3 and 15 mol% AgOTf at 60 • C in ClCH 2 CH 2 Cl.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 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% AuBr 3 and fifteen mol% AgOTf were added at room temperature to a solution of N-tosylpropargyl amine 1 and 1,3-dicarbonyl compound 2 in ClCH 2 CH 2 Cl, 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 SiO 2 column chromatography (eluents = hexane:AcOEt or diethyl ether) to give poly-substituted furan 3.
The 1 H-NMR and 13 C-NMR data are identical to the reported values [9].

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.

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.

Table 2 .
Effect of the counter anion of silver catalyst in gold(III)-catalyzed propargylic substitution reaction followed by cycloisomerization.