Synthesis of 2-Benzylidene-3-Pyrrolines and Their Synthetic Transformation Synthesis of 2-Benzylidene-3-Pyrrolines and Their Synthetic Transformation

: A series of benzylidene-3-pyrrolines were prepared from chalcone derivatives, arylacetylene and sulfonamide via a three-step sequence without the isolation of intermediates. Typically, the reaction of 1,3-di- p -tolylprop-2-en-1-one with lithium phenylacetylide was followed by substitution with tosylamide and then silver-catalyzed 5-exo-dig cyclization to give N -tosyl-2-benzylidene-3,5-di- p -tolyl-2,5-dihydro-1 H -pyrrole with a 86% yield. Furthermore, transformation to the corresponding substituted 3-pyrrolin-2-one and pyrrole by m -chloroperbenzoic acid (mcpba)-oxidation and acid-catalyzed aromatization, respectively, was investigated. nature [1–3] and pharmaceuticals [4–8]. A few examples of their biological activity are shown in Figure 1. Although the synthetic methods leading to pyrrole and / or pyrroline rings are well-documented, there is still a demand for developing new approaches for highly substituted and functionalized compounds. Abstract: A series of benzylidene-3-pyrrolines were prepared from chalcone derivatives, arylacetylene and sulfonamide via a three-step sequence without the isolation of intermediates. Typically, the reaction of 1,3-di- p -tolylprop-2-en-1-one with lithium phenylacetylide was followed by substitution with tosylamide and then silver-catalyzed 5-exo-dig cyclization to give N -tosyl-2-benzylidene-3,5-di- p -tolyl-2,5-dihydro-1 H -pyrrole with a 86% yield. Furthermore, transformation to the corresponding substituted 3-pyrrolin-2-one and pyrrole by m -chloroperbenzoic acid (mcpba)-oxidation and acid-catalyzed aromatization, respectively, was investigated. methodology, investigation and data collection, M.-T.H.; crystallography, Y.-H.L.; writing—original draft preparation, S.-T.L.; writing—review and editing, M.-T.H. and S.-T.L.; supervision, S.-T.L.; S.-T.L.

A few examples of their biological activity are shown in Figure 1. Although the synthetic methods leading to pyrrole and/or pyrroline rings are well-documented, there is still a demand for developing new approaches for highly substituted and functionalized compounds.
A few examples of their biological activity are shown in Figure 1. Although the synthetic methods leading to pyrrole and/or pyrroline rings are well-documented, there is still a demand for developing new approaches for highly substituted and functionalized compounds. In this context, 3-ylidene-1-pyrrolines (I) have received much attention, because of the presence of an exocyclic double bond, a reactive imine bond and a nucleophilic nitrogen site on the ring [9]. Thus, various transformations of these compounds leading to pyrrole derivatives have been disclosed. On the other hand, 2-ylidene-3-pyrrolines (II), isomeric structures of I (when R" = H), are In this context, 3-ylidene-1-pyrrolines (I) have received much attention, because of the presence of an exocyclic double bond, a reactive imine bond and a nucleophilic nitrogen site on the ring [9]. Thus, various transformations of these compounds leading to pyrrole derivatives have been disclosed. On the other hand, 2-ylidene-3-pyrrolines (II), isomeric structures of I (when R" = H), are less explored [10][11][12]. Quite a few reports show that 2-ylidene-3-pyrrolines are reactive intermediates and undergo aromatization upon heating to render the corresponding pyrroles [13]. In this work, we would like to investigate the possibility of the cyclization of (Z)-2-en-4-yn-1-amines (III) to give 2-ylidene-3-pyrroline and then their further transformation.

Materials and Instrumentation
All chemicals were purchased and used without any further purification. Flash chromatography was performed using a silica gel 230-400 mesh. Nuclear magnetic resonance spectra were recorded in CDCl 3 or acetone-d 6 on either a Bruker AM-300 or AVANCE 400 spectrometer (Bruker BioSpin Corporation, Billerica, MA, USA). Chemical shifts are given in parts per million relative to Me 4 Si for 1 H and 13 C{ 1 H} NMR. Infrared spectra were measured on a Nicolet Magna-IR 550 spectrometer (Series-II) (Spectralab, ON, Canada) as KBr pellets, unless otherwise noted.

Synthesis
A solution of 2.5 M n-butyllithium (0.4 mL, 1.0 mmol) was added to a solution of phenylacetylene (1.0 mmol) in tetrahydrofuran (THF, 4 mL) at the temperature of a dry-ice/acetone bath. Chalcone (0.4 mmol) in pre-dried THF (2 mL) was slowly added to the above solution. After addition, the reaction mixture was heated to reflux for 4 h. Upon cooling, ether (10 mL) was added and the mixture was washed with saturated ammonium chloride solution and water. The organic portion was dried over magnesium sulfate and concentrated under reduced pressure. The crude product 2 was subjected to the next step.
A solution of toluenesulfonamide (1.2 mmol) and sulfuric acid (60 µL, 1.2 mmol) in THF (2 mL) was warmed to 50 • C. The crude 2 from the last step in THF (0.5 mL) was slowly added to the above solution and kept at 50 • C for several hours. Ether (10 mL) was then added, and the mixture was washed with saturated sodium hydrogen carbonate solution and water. The organic portion was dried over magnesium sulfate and concentrated under reduced pressure to give crude product 3.
Compound 3 from the last step was dissolved in dichloromethane (2 mL), and Ag(CH 3 COO) (6.7 mg, 0.04 mmol) and triphenylphosphine (10.5 mg, 0.04 mmol) in methanol (2 mL) were then added to the above solution slowly. After addition, the mixture was heated at 60 • C for several hours. Upon cooling, the solution was concentrated to give the crude products, which were chromatographed on silica gel with the elution of dichloromethane/hexane to give the final pure product.

Synthetic Design
The synthetic scheme leading to the target molecule 4 is illustrated in Scheme 1. In order to have 2-en-4-ynilamine (3) for the cyclization study, we envision that the S N 2' substitution of 1-en-4-yn-3-ol (2) with a nitrogen nucleophile would be a good approach, because 2 is readily available from the addition of acetylide with a chalcone molecule 1 (Scheme 2). Another important advantage of this approach is that the starting chalcone compounds are commercially available or prepared by aldol condensation reactions.

Optimization of Each Step
Our ultimate goal is to carry out this three-step reaction sequentially without the isolation and purification of products in each step. However, it is necessary to have optimized reaction conditions for each step. Accordingly, the first step in preparing compound 2a (R = C6H5; Ar = Ar' = p-CH3C6H4-) is achieved by the addition of an equal molar amount of acetylide anion to a solution of 1a (Ar = Ar' = p-CH3C6H4-) in THF at the temperature of a dry-ice/acetone bath. A simple workup by extraction gave 2a with a quantitative yield.
The substitution of 2a with various nitrogen nucleophiles was then investigated, and it appears to be a challenge (Scheme 3). When p-toluidine was used as the nucleophile, the substrate was consumed within a few hours in the presence of 30 mol% of H2SO4, but the desired product 5 was obtained in trace amounts. Interestingly, the use of N-methylaniline as the reagent gave an electrophilic aromatic substitution product, 6. Obviously, the carbocation intermediate int-1 produced via the acid-promoted dissociation of 2a follows the electrophilic substitution with the aromatic ring instead of a combination with the nitrogen donor of N-methylaniline. Finally, the treatment of 2a in a THF solution with p-toluenesulfonamide in the presence of sulfuric acid at 50 °C gave the desired substitution product 7, quantitatively.

Scheme 1. Structure of ylidene-pyrrolines.
Reactions 2020, 3, x FOR PEER REVIEW 3 of 7 approach is that the starting chalcone compounds are commercially available or prepared by aldol condensation reactions. Scheme 1. Structure of ylidene-pyrrolines.

Optimization of Each Step
Our ultimate goal is to carry out this three-step reaction sequentially without the isolation and purification of products in each step. However, it is necessary to have optimized reaction conditions for each step. Accordingly, the first step in preparing compound 2a (R = C6H5; Ar = Ar' = p-CH3C6H4-) is achieved by the addition of an equal molar amount of acetylide anion to a solution of 1a (Ar = Ar' = p-CH3C6H4-) in THF at the temperature of a dry-ice/acetone bath. A simple workup by extraction gave 2a with a quantitative yield.
The substitution of 2a with various nitrogen nucleophiles was then investigated, and it appears to be a challenge (Scheme 3). When p-toluidine was used as the nucleophile, the substrate was consumed within a few hours in the presence of 30 mol% of H2SO4, but the desired product 5 was obtained in trace amounts. Interestingly, the use of N-methylaniline as the reagent gave an electrophilic aromatic substitution product, 6. Obviously, the carbocation intermediate int-1 produced via the acid-promoted dissociation of 2a follows the electrophilic substitution with the aromatic ring instead of a combination with the nitrogen donor of N-methylaniline. Finally, the treatment of 2a in a THF solution with p-toluenesulfonamide in the presence of sulfuric acid at 50 °C gave the desired substitution product 7, quantitatively. Scheme 2. Our synthetic approach.

Optimization of Each Step
Our ultimate goal is to carry out this three-step reaction sequentially without the isolation and purification of products in each step. However, it is necessary to have optimized reaction conditions for each step. Accordingly, the first step in preparing compound 2a (R = C 6 H 5 ; Ar = Ar' = p-CH 3 C 6 H 4 -) is achieved by the addition of an equal molar amount of acetylide anion to a solution of 1a (Ar = Ar' = p-CH 3 C 6 H 4 -) in THF at the temperature of a dry-ice/acetone bath. A simple workup by extraction gave 2a with a quantitative yield.
The substitution of 2a with various nitrogen nucleophiles was then investigated, and it appears to be a challenge (Scheme 3). When p-toluidine was used as the nucleophile, the substrate was consumed within a few hours in the presence of 30 mol% of H 2 SO 4 , but the desired product 5 was obtained in trace amounts. Interestingly, the use of N-methylaniline as the reagent gave an electrophilic aromatic substitution product, 6. Obviously, the carbocation intermediate int-1 produced via the acid-promoted dissociation of 2a follows the electrophilic substitution with the aromatic ring instead of a combination with the nitrogen donor of N-methylaniline. Finally, the treatment of 2a in a THF solution with p-toluenesulfonamide in the presence of sulfuric acid at 50 • C gave the desired substitution product 7, quantitatively.
With compound 7 in hand, the cyclization reaction leading to the desired product under various catalytic conditions was examined ( Table 1). As shown in the table, it was revealed that silver ion is a suitable catalyst for promoting the cyclization, and the best reaction condition is carrying out the reaction in the presence of triphenylphosphine ligand in a mixed solvent at 60 • C (Table 1, entry 6). It is observable that the use of phosphine ligand readily assists the catalytic cyclization. Presumably, the triphenylphosphine ligand is able to stabilize the intermediate and diminish the decomposition of the metal complex. The reaction proceeds via a 5-exo-dig cyclization, instead of a 6-endo-dig pathway, to yield the five-membered ring product. With compound 7 in hand, the cyclization reaction leading to the desired product under various catalytic conditions was examined ( Table 1). As shown in the table, it was revealed that silver ion is a suitable catalyst for promoting the cyclization, and the best reaction condition is carrying out the reaction in the presence of triphenylphosphine ligand in a mixed solvent at 60 °C (Table 1, entry 6). It is observable that the use of phosphine ligand readily assists the catalytic cyclization. Presumably, the triphenylphosphine ligand is able to stabilize the intermediate and diminish the decomposition of the metal complex. The reaction proceeds via a 5-exo-dig cyclization, instead of a 6-endo-dig pathway, to yield the five-membered ring product.   With compound 7 in hand, the cyclization reaction leading to the desired product under various catalytic conditions was examined ( Table 1). As shown in the table, it was revealed that silver ion is a suitable catalyst for promoting the cyclization, and the best reaction condition is carrying out the reaction in the presence of triphenylphosphine ligand in a mixed solvent at 60 °C (Table 1, entry 6). It is observable that the use of phosphine ligand readily assists the catalytic cyclization. Presumably, the triphenylphosphine ligand is able to stabilize the intermediate and diminish the decomposition of the metal complex. The reaction proceeds via a 5-exo-dig cyclization, instead of a 6-endo-dig pathway, to yield the five-membered ring product.

Reaction Scope
With the understanding of the reaction conditions of each step, a sequential process without the purification of the product of each step was attempted, and compound 4a was chosen as the target. As described in detail in Section 2.2, compound 4a was obtained with an 86% isolated yield. Thus, various substituted chalcones were subjected to this reaction sequence accordingly, to render the expected products with good-to-excellent yields ( Table 2). All the compounds obtained were characterized by NMR and mass analyses, and the structure of 4a was further confirmed by X-ray crystallography ( Figure S1). purification of the product of each step was attempted, and compound 4a was chosen as the target. As described in detail in Section 2.2, compound 4a was obtained with an 86% isolated yield. Thus, various substituted chalcones were subjected to this reaction sequence accordingly, to render the expected products with good-to-excellent yields ( Table 2). All the compounds obtained were characterized by NMR and mass analyses, and the structure of 4a was further confirmed by X-ray crystallography ( Figure S1).  Instead of p-toluenesulfonamide, methanesulfonamide is also a good nitrogen nucleophile for the reaction. Two examples of the mesylated products 8a-b are illustrated in Scheme 4. In addition, trimethylsilylacetylene is also suitable for this sequential reaction to give 9 as the single product. It is noticed that the trimethylsilyl group was removed under the reaction conditions (Scheme 4).

Further Synthetic Transformation
Next, we studied the synthetic application of the obtained 2-ylidene-3-pyrrolines (Scheme 5). As expected, in the presence of acid, compound 4a readily underwent C=C double migration to give the Instead of p-toluenesulfonamide, methanesulfonamide is also a good nitrogen nucleophile for the reaction. Two examples of the mesylated products 8a-b are illustrated in Scheme 4. In addition, trimethylsilylacetylene is also suitable for this sequential reaction to give 9 as the single product. It is noticed that the trimethylsilyl group was removed under the reaction conditions (Scheme 4).
expected products with good-to-excellent yields ( Table 2). All the compounds obtained were characterized by NMR and mass analyses, and the structure of 4a was further confirmed by X-ray crystallography ( Figure S1). Instead of p-toluenesulfonamide, methanesulfonamide is also a good nitrogen nucleophile for the reaction. Two examples of the mesylated products 8a-b are illustrated in Scheme 4. In addition, trimethylsilylacetylene is also suitable for this sequential reaction to give 9 as the single product. It is noticed that the trimethylsilyl group was removed under the reaction conditions (Scheme 4).

Further Synthetic Transformation
Next, we studied the synthetic application of the obtained 2-ylidene-3-pyrrolines (Scheme 5). As expected, in the presence of acid, compound 4a readily underwent C=C double migration to give the

Further Synthetic Transformation
Next, we studied the synthetic application of the obtained 2-ylidene-3-pyrrolines (Scheme 5). As expected, in the presence of acid, compound 4a readily underwent C=C double migration to give the corresponding pyrrole compound 10 at room temperature. Presumably, the driving force for this double bond migration comes from the aromaticity of the pyrrole ring. When the reaction was carried out with the use of BF 3 as the acid catalyst at 60 • C, the pyrrole compound 11 was still formed with a 96% yield according to NMR determination. However, it is observable that the migration of the tosyl group to the 3-position of the ring occurred to yield the tosyl-substituted pyrrole 11 [14,15]. Compound 11 was treated with Boc 2 O in the presence of a base to give N-Boc-protected pyrrole 11', which crystallized to give a single crystal form for X-ray analysis. Thus, crystallographic determination confirmed the structure of 11, i.e., the 3-position of the tosyl group in the ring. The oxidation of 4a with mcpba (m-chloroperbenzoic acid) produced the α,β-unsaturated γ-lactam 12 with a reasonable yield.
96% yield according to NMR determination. However, it is observable that the migration of the tosyl group to the 3-position of the ring occurred to yield the tosyl-substituted pyrrole 11 [14,15]. Compound 11 was treated with Boc2O in the presence of a base to give N-Boc-protected pyrrole 11', which crystallized to give a single crystal form for X-ray analysis. Thus, crystallographic determination confirmed the structure of 11, i.e., the 3-position of the tosyl group in the ring. The oxidation of 4a with mcpba (m-chloroperbenzoic acid) produced the α,β-unsaturated γ-lactam 12 with a reasonable yield. Scheme 5. Synthetic transformation of 2-ylidene-3-pyrrolines.

Conclusions
In this study, we succeeded in the preparation of 2-ylidene-3-pyrrolines via a three-step reaction without the purification of intermediates. In addition, the synthetic transformation of these compounds into the corresponding pyrrole, tosyl-substituted pyrrole and α,β-unsaturated γ-lactam was demonstrated. This development offers a synthetic approach to producing highly substituted pyrrole derivatives, which are useful for further application.