Synthesis of Multi-Substituted Pyrrole Derivatives Through [3+2] Cycloaddition with Tosylmethyl Isocyanides (TosMICs) and Electron-Deficient Compounds

Pyrrole and its polysubstituted derivatives are important five-membered heterocyclic compounds, which exist alone or as a core framework in many pharmaceutical and natural product structures, some of which have good biological activities. The Van Leusen [3+2] cycloaddition reaction based on tosylmethyl isocyanides (TosMICs) and electron-deficient compounds as a substrate, which has been continuously developed due to its advantages such as operationally simple, easily available starting materials, and broadly range of substrates, is one of the most convenient methods to synthetize pyrrole heterocycles. In this review, we discuss the different types of two carbon synthons in the Van Leusen pyrrole reaction and give a summary of the progress of these synthesis methods in the past two decades.


Introduction
Pyrrole and its polysubstituted derivatives are important five-membered heterocyclic compounds, which exist alone or as a core skeleton in many pharmaceutical and natural product structures, some of them have good bioactivity such as antibacterial [1,2], antifungal [3,4], anti-inflammatory [5,6], antiviral [7], antimalarial [8], anticancer [9,10], antiparasitic [11], etc., and can also be used as enzyme inhibitor in the organism [12,13]. Some typical pyrrole derivative chemical structures and the physiological functions are summarized in the following Table 1.
Since pyrrole and its multi-substituted derivatives play an important role in organic synthesis as well as in biology, syntheses of five-membered heterocyclic pyrrole compounds have always been valued by researchers. Over the last decades, there are many methods for synthesizing pyrrole compounds in laboratory routes [14], and the classical methods include Knorr pyrrole synthesis [15], Paal-Knorr pyrrole synthesis [16], Hantzsch pyrrole synthesis [17], Barton-Zard reaction [18], Van Leusen pyrrole synthesis [19], and Piloty-Robinson pyrrole synthesis [20]. These synthesis methods are summarized in Scheme 1. Table 1. Some typical pyrrole derivative chemical structures and the physiological functions.

Physiological Functions
In recent reports, it has been found that this reaction occurs selectively at the position of a less polar double bond. The use of electron-deficient compounds having an electron-withdrawing group and a relatively stable structure, or a solvation effect in the reaction system to stabilize the structure of the electron-deficient compound, can significantly increase the rate and yield of the reactions. Scheme 1. Typical cycloaddition methods for pyrrole heterocycle and its derivatives.
As shown in Scheme 1, the method for synthesizing pyrrole based on the [3+2] cycloaddition reaction of TosMIC as 3-atom synthon with electron-deficient olefins is also known as the Van Leusen pyrrole synthesis. It was first reported by the Van Leusen et al. in 1972. Van Leusen and co-workers used TosMICs with ester-containing double bond compounds to synthesize a series of 3,4-disubstituted pyrrole compounds under basic conditions [19]. Subsequently, they extended the substrate scope to include electron-withdrawing groups on electron-deficient olefins, such as α,β-unsaturated cyano, sulfonyl, nitro, and sulfonyl groups, which enriched the structure diversity of the resulting pyrrole compounds [21,22]. Therefore, the Van Leusen [3+2] cycloaddition reaction is one of the most convenient methods to synthetize pyrrole heterocycles, which has been continuously developed over the ensuing years due to its advantages such as operationally simple, easily available starting materials, and broad range of substrates.
TosMIC is a colorless, odorless, stable solid that can be stored at room temperature. It is an important organic synthesis intermediate, and widely used in the synthesis of five-membered nitrogen-containing heterocycles [23]. Under the Van Leusen pyrrole synthesis reaction conditions, TosMIC loses a proton to form a carbanion under the action of a base because of the electron-withdrawing effect of the sulfone and isocyanide. The carbon anion attacks on the α,β-unsaturated compound, undergoes an intramolecular [3+2] cycloaddition reaction, and causes the leaving of the tosyl group to form the final heterocyclic compound. The mechanism of [3+2] cycloaddition reaction between TosMICs and electron-deficient alkenes to form pyrrole derivatives is shown in Scheme 2.
Molecules 2018, 23 As shown in Scheme 1, the method for synthesizing pyrrole based on the [3+2] cycloaddition reaction of TosMIC as 3-atom synthon with electron-deficient olefins is also known as the Van Leusen pyrrole synthesis. It was first reported by the Van Leusen et al. in 1972. Van Leusen and co-workers used TosMICs with ester-containing double bond compounds to synthesize a series of 3,4disubstituted pyrrole compounds under basic conditions [19]. Subsequently, they extended the substrate scope to include electron-withdrawing groups on electron-deficient olefins, such as α,βunsaturated cyano, sulfonyl, nitro, and sulfonyl groups, which enriched the structure diversity of the resulting pyrrole compounds [21,22]. Therefore，the Van Leusen [3+2] cycloaddition reaction is one of the most convenient methods to synthetize pyrrole heterocycles, which has been continuously developed over the ensuing years due to its advantages such as operationally simple, easily available starting materials, and broad range of substrates.
TosMIC is a colorless, odorless, stable solid that can be stored at room temperature. It is an important organic synthesis intermediate, and widely used in the synthesis of five-membered nitrogen-containing heterocycles [23]. Under the Van Leusen pyrrole synthesis reaction conditions, TosMIC loses a proton to form a carbanion under the action of a base because of the electronwithdrawing effect of the sulfone and isocyanide. The carbon anion attacks on the α,β-unsaturated compound, undergoes an intramolecular [3+2] cycloaddition reaction, and causes the leaving of the tosyl group to form the final heterocyclic compound. The mechanism of [3+2] cycloaddition reaction between TosMICs and electron-deficient alkenes to form pyrrole derivatives is shown in Scheme 2. In recent reports, it has been found that this reaction occurs selectively at the position of a less polar double bond. The use of electron-deficient compounds having an electron-withdrawing group and a relatively stable structure, or a solvation effect in the reaction system to stabilize the structure of the electron-deficient compound, can significantly increase the rate and yield of the reactions. In recent reports, it has been found that this reaction occurs selectively at the position of a less polar double bond. The use of electron-deficient compounds having an electron-withdrawing group and a relatively stable structure, or a solvation effect in the reaction system to stabilize the structure of the electron-deficient compound, can significantly increase the rate and yield of the reactions.
In this paper, we review the research progress of the synthesis of pyrrole derivatives through the [3+2] cycloaddition reaction between TosMICs and different kinds of 2-carbon synthons based on the Van Leusen pyrrole synthesis method in the past two decades.

Synthesis of Pyrrole Derivatives by [3+2] Cycloaddition of TosMICs with Alkenes
In 1972, Van Leusen and co-workers firstly reported that TosMICs can react with electron-deficient alkenes under basic conditions to produce 3-substituted pyrrole derivatives [19]. They found that there are [3+2] cycloadditions occurring in alkenes with different electron-withdrawing groups. As shown in Scheme 3, the electron-withdrawing groups may be esters, amides, ketones, nitros, cyanos, aryls, etc. . Based on the different types of electron-withdrawing group attached to the alkenes, they are classified and described in order (Scheme 3).
Molecules 2018, 23, x FOR PEER REVIEW 4 of 19 In this paper, we review the research progress of the synthesis of pyrrole derivatives through the [3+2] cycloaddition reaction between TosMICs and different kinds of 2-carbon synthons based on the Van Leusen pyrrole synthesis method in the past two decades.

Synthesis of Pyrrole Derivatives by [3+2] Cycloaddition of TosMICs with Alkenes
In 1972, Van Leusen and co-workers firstly reported that TosMICs can react with electrondeficient alkenes under basic conditions to produce 3-substituted pyrrole derivatives [19]. They found that there are [3+2] cycloadditions occurring in alkenes with different electronwithdrawing groups. As shown in Scheme 3, the electron-withdrawing groups may be esters, amides, ketones, nitros, cyanos, aryls, etc. . Based on the different types of electronwithdrawing group attached to the alkenes, they are classified and described in order (Scheme 3). Scheme 3. Synthetic protocols for polysubstituted pyrroles from TosMICs and electron-defect alkenes.

Alkenes with an Ester Group
As early as in the 1990s, Van Leusen and co-workers developed a process in which TosMIC 16 reacts with a Michael acceptor to form 3,4-disubstituted pyrrole compounds 17 or 3-substituted pyrrole compounds 18. This procedure necessarily installs the activating Z group of the Michael acceptor at the 3-position of the pyrrole ring formed (Scheme 4) [22,24]. In 1997, the Trudell group described an expeditious method for the synthesis of 3-arylsubstituted pyrroles. The 3-arylpyrroles 22 were prepared in a short reaction sequence from the readily available aryl aldehydes 19. The aldehydes 19 were converted into the corresponding methyl 3-arylacrylate esters 20 using a Wadsworth-Emmons olefination procedure. Treatment of 20 with TosMIC 16 afforded the 4-aryl-3-(methoxycarbonyl)-pyrroles 21. Then the ester moieties were hydrolyzed to the corresponding carboxylic acids with excess KOH in 50% MeOH. The acid derivatives were then decarboxylated by heating in 2-ethanolamine to give the 3-arylpyrroles 22 in good yield (Scheme 5) [25].

Alkenes with an Ester Group
As early as in the 1990s, Van Leusen and co-workers developed a process in which TosMIC 16 reacts with a Michael acceptor to form 3,4-disubstituted pyrrole compounds 17 or 3-substituted pyrrole compounds 18. This procedure necessarily installs the activating Z group of the Michael acceptor at the 3-position of the pyrrole ring formed (Scheme 4) [22,24]. In this paper, we review the research progress of the synthesis of pyrrole derivatives through the [3+2] cycloaddition reaction between TosMICs and different kinds of 2-carbon synthons based on the Van Leusen pyrrole synthesis method in the past two decades.

Synthesis of Pyrrole Derivatives by [3+2] Cycloaddition of TosMICs with Alkenes
In 1972, Van Leusen and co-workers firstly reported that TosMICs can react with electrondeficient alkenes under basic conditions to produce 3-substituted pyrrole derivatives [19]. They found that there are [3+2] cycloadditions occurring in alkenes with different electronwithdrawing groups. As shown in Scheme 3, the electron-withdrawing groups may be esters, amides, ketones, nitros, cyanos, aryls, etc. . Based on the different types of electronwithdrawing group attached to the alkenes, they are classified and described in order (Scheme 3). Scheme 3. Synthetic protocols for polysubstituted pyrroles from TosMICs and electron-defect alkenes.

Alkenes with an Ester Group
As early as in the 1990s, Van Leusen and co-workers developed a process in which TosMIC 16 reacts with a Michael acceptor to form 3,4-disubstituted pyrrole compounds 17 or 3-substituted pyrrole compounds 18. This procedure necessarily installs the activating Z group of the Michael acceptor at the 3-position of the pyrrole ring formed (Scheme 4) [22,24]. In 1997, the Trudell group described an expeditious method for the synthesis of 3-arylsubstituted pyrroles. The 3-arylpyrroles 22 were prepared in a short reaction sequence from the readily available aryl aldehydes 19. The aldehydes 19 were converted into the corresponding methyl 3-arylacrylate esters 20 using a Wadsworth-Emmons olefination procedure. Treatment of 20 with TosMIC 16 afforded the 4-aryl-3-(methoxycarbonyl)-pyrroles 21. Then the ester moieties were hydrolyzed to the corresponding carboxylic acids with excess KOH in 50% MeOH. The acid derivatives were then decarboxylated by heating in 2-ethanolamine to give the 3-arylpyrroles 22 in good yield (Scheme 5) [25].  In 1997, the Trudell group described an expeditious method for the synthesis of 3-aryl-substituted pyrroles. The 3-arylpyrroles 22 were prepared in a short reaction sequence from the readily available aryl aldehydes 19. The aldehydes 19 were converted into the corresponding methyl 3-arylacrylate esters 20 using a Wadsworth-Emmons olefination procedure. Treatment of 20 with TosMIC 16 afforded the 4-aryl-3-(methoxycarbonyl)-pyrroles 21. Then the ester moieties were hydrolyzed to the corresponding carboxylic acids with excess KOH in 50% MeOH. The acid derivatives were then decarboxylated by heating in 2-ethanolamine to give the 3-arylpyrroles 22 in good yield (Scheme 5) [25]. In this paper, we review the research progress of the synthesis of pyrrole derivatives through the [3+2] cycloaddition reaction between TosMICs and different kinds of 2-carbon synthons based on the Van Leusen pyrrole synthesis method in the past two decades.

Synthesis of Pyrrole Derivatives by [3+2] Cycloaddition of TosMICs with Alkenes
In 1972, Van Leusen and co-workers firstly reported that TosMICs can react with electrondeficient alkenes under basic conditions to produce 3-substituted pyrrole derivatives [19]. They found that there are [3+2] cycloadditions occurring in alkenes with different electronwithdrawing groups. As shown in Scheme 3, the electron-withdrawing groups may be esters, amides, ketones, nitros, cyanos, aryls, etc. . Based on the different types of electronwithdrawing group attached to the alkenes, they are classified and described in order (Scheme 3). Scheme 3. Synthetic protocols for polysubstituted pyrroles from TosMICs and electron-defect alkenes.

Alkenes with an Ester Group
As early as in the 1990s, Van Leusen and co-workers developed a process in which TosMIC 16 reacts with a Michael acceptor to form 3,4-disubstituted pyrrole compounds 17 or 3-substituted pyrrole compounds 18. This procedure necessarily installs the activating Z group of the Michael acceptor at the 3-position of the pyrrole ring formed (Scheme 4) [22,24]. In 1997, the Trudell group described an expeditious method for the synthesis of 3-arylsubstituted pyrroles. The 3-arylpyrroles 22 were prepared in a short reaction sequence from the readily available aryl aldehydes 19. The aldehydes 19 were converted into the corresponding methyl 3-arylacrylate esters 20 using a Wadsworth-Emmons olefination procedure. Treatment of 20 with TosMIC 16 afforded the 4-aryl-3-(methoxycarbonyl)-pyrroles 21. Then the ester moieties were hydrolyzed to the corresponding carboxylic acids with excess KOH in 50% MeOH. The acid derivatives were then decarboxylated by heating in 2-ethanolamine to give the 3-arylpyrroles 22 in good yield (Scheme 5) [25].
The electron neutral or electron-deficient aryl vinyl esters such as cinnamic acid esters could be successfully employed in the cyclization reaction. However, the TosMIC 16 addition reaction with 20 which possessed electron-rich substituents on the aryl ring did not yield the desired pyrroles, but rather gave intractable mixtures.
The In 2007, Krishna's group found that aldehyde 28 on treatment with (ethoxycarbonylmethylene)triphenylphosphorane in refluxing benzene was converted to the α,β-unsaturated ester 29 (72%), and treatment of 29 with potassium salt of TosMIC 16 afforded the corresponding pyrrole C-nucleosides 30a (36%) and 30b (32%) (Scheme 7) [27]. In 2008, Shin's group developed a synthesis of ethyl 4-substituted-1H-pyrrole-3-carboxylates 33 from aldehyde 31, in which they synthesized α,β-unsaturated ester 32 from aromatic or aliphatic aldehydes by the Horner-Wadsworth-Emmons reaction and subsequently reacted it with TosMIC 16 in the presence of sodium t-amylate in toluene. In this reaction, the solvent, toluene, can be used in both reaction and crystallization, which makes it more practical and greener (Scheme 8) [28]. In 2008, Shin's group developed a synthesis of ethyl 4-substituted-1H-pyrrole-3-carboxylates 33 from aldehyde 31, in which they synthesized α,β-unsaturated ester 32 from aromatic or aliphatic aldehydes by the Horner-Wadsworth-Emmons reaction and subsequently reacted it with TosMIC 16 in the presence of sodium t-amylate in toluene. In this reaction, the solvent, toluene, can be used in both reaction and crystallization, which makes it more practical and greener (Scheme 8) [28]. Hu's group developed a procedure for the preparation of N-arylated 3,4-disubstituted pyrroles 35 from alkenes in the same year. They found that these compounds can be obtained when a mixture of ethyl 3-phenylacrylate 34, TosMIC 16, PhI, CuI, and 1,10-phenanthroline in toluene was treated with 3.0 equivalents of base at −30 °C for 10 min and then the resultant mixture was refluxed until the intermediate was completely exhausted. When a (1:2) mixture of t-BuONa to Cs2CO3 was used as base, 35 was obtained as a single product. In this procedure, t-BuONa served as a base for Van Leusen pyrrole synthesis and Cs2CO3 for the N-arylation, respectively (Scheme 9) [29]. In the same year, the Sánchez-García group reported that 2,2′-bipyrroles compounds 43 were synthesized through the reaction of enesters 42 and TosMIC 16. 2,7,12,17-tetraarylporphycenes 44 can be synthesized by using compounds 43 as raw materials. Porphycenes are of great value in the chemical industry and in biomedicine. During this reaction, there will also be a monopyrrole product formed, but if post-treated with dilute ammonia, the bipyrrole compound can be precipitated in ethyl acetate (Scheme 11) [31].  Hu's group developed a procedure for the preparation of N-arylated 3,4-disubstituted pyrroles 35 from alkenes in the same year. They found that these compounds can be obtained when a mixture of ethyl 3-phenylacrylate 34, TosMIC 16, PhI, CuI, and 1,10-phenanthroline in toluene was treated with 3.0 equivalents of base at −30 • C for 10 min and then the resultant mixture was refluxed until the intermediate was completely exhausted. When a (1:2) mixture of t-BuONa to Cs 2 CO 3 was used as base, 35 was obtained as a single product. In this procedure, t-BuONa served as a base for Van Leusen pyrrole synthesis and Cs 2 CO 3 for the N-arylation, respectively (Scheme 9) [29]. Hu's group developed a procedure for the preparation of N-arylated 3,4-disubstituted pyrroles 35 from alkenes in the same year. They found that these compounds can be obtained when a mixture of ethyl 3-phenylacrylate 34, TosMIC 16, PhI, CuI, and 1,10-phenanthroline in toluene was treated with 3.0 equivalents of base at −30 °C for 10 min and then the resultant mixture was refluxed until the intermediate was completely exhausted. When a (1:2) mixture of t-BuONa to Cs2CO3 was used as base, 35 was obtained as a single product. In this procedure, t-BuONa served as a base for Van Leusen pyrrole synthesis and Cs2CO3 for the N-arylation, respectively (Scheme 9) [29]. In the same year, the Sánchez-García group reported that 2,2′-bipyrroles compounds 43 were synthesized through the reaction of enesters 42 and TosMIC 16. 2,7,12,17-tetraarylporphycenes 44 can be synthesized by using compounds 43 as raw materials. Porphycenes are of great value in the chemical industry and in biomedicine. During this reaction, there will also be a monopyrrole product formed, but if post-treated with dilute ammonia, the bipyrrole compound can be precipitated in ethyl acetate (Scheme 11) [31].  Hu's group developed a procedure for the preparation of N-arylated 3,4-disubstituted pyrroles 35 from alkenes in the same year. They found that these compounds can be obtained when a mixture of ethyl 3-phenylacrylate 34, TosMIC 16, PhI, CuI, and 1,10-phenanthroline in toluene was treated with 3.0 equivalents of base at −30 °C for 10 min and then the resultant mixture was refluxed until the intermediate was completely exhausted. When a (1:2) mixture of t-BuONa to Cs2CO3 was used as base, 35 was obtained as a single product. In this procedure, t-BuONa served as a base for Van Leusen pyrrole synthesis and Cs2CO3 for the N-arylation, respectively (Scheme 9) [29]. In the same year, the Sánchez-García group reported that 2,2′-bipyrroles compounds 43 were synthesized through the reaction of enesters 42 and TosMIC 16. 2,7,12,17-tetraarylporphycenes 44 can be synthesized by using compounds 43 as raw materials. Porphycenes are of great value in the chemical industry and in biomedicine. During this reaction, there will also be a monopyrrole product formed, but if post-treated with dilute ammonia, the bipyrrole compound can be precipitated in ethyl acetate (Scheme 11) [31].  In the same year, the Sánchez-García group reported that 2,2 -bipyrroles compounds 43 were synthesized through the reaction of enesters 42 and TosMIC 16. 2,7,12,17-tetraarylporphycenes 44 can be synthesized by using compounds 43 as raw materials. Porphycenes are of great value in the chemical industry and in biomedicine. During this reaction, there will also be a monopyrrole product formed, but if post-treated with dilute ammonia, the bipyrrole compound can be precipitated in ethyl acetate (Scheme 11) [31]. Hu's group developed a procedure for the preparation of N-arylated 3,4-disubstituted pyrroles 35 from alkenes in the same year. They found that these compounds can be obtained when a mixture of ethyl 3-phenylacrylate 34, TosMIC 16, PhI, CuI, and 1,10-phenanthroline in toluene was treated with 3.0 equivalents of base at −30 °C for 10 min and then the resultant mixture was refluxed until the intermediate was completely exhausted. When a (1:2) mixture of t-BuONa to Cs2CO3 was used as base, 35 was obtained as a single product. In this procedure, t-BuONa served as a base for Van Leusen pyrrole synthesis and Cs2CO3 for the N-arylation, respectively (Scheme 9) [29]. In the same year, the Sánchez-García group reported that 2,2′-bipyrroles compounds 43 were synthesized through the reaction of enesters 42 and TosMIC 16. 2,7,12,17-tetraarylporphycenes 44 can be synthesized by using compounds 43 as raw materials. Porphycenes are of great value in the chemical industry and in biomedicine. During this reaction, there will also be a monopyrrole product formed, but if post-treated with dilute ammonia, the bipyrrole compound can be precipitated in ethyl acetate (Scheme 11) [31]. In 2018, the Lamberth group reported a new synthesis route of pyrrolocarboxamide compounds 57. They firstly used diethyl maleate 55 as starting material, which was converted with TosMIC 16 into the 3,4-dicarbethoxy-substituted pyrrole 56. Then, after a series of reactions on the substituents, pyrrole carboxamide compound 57 was synthesized (Scheme 15) [35]. In 2018, the Lamberth group reported a new synthesis route of pyrrolocarboxamide compounds 57. They firstly used diethyl maleate 55 as starting material, which was converted with TosMIC 16 into the 3,4-dicarbethoxy-substituted pyrrole 56. Then, after a series of reactions on the substituents, pyrrole carboxamide compound 57 was synthesized (Scheme 15) [35]. In 2018, the Lamberth group reported a new synthesis route of pyrrolocarboxamide compounds 57. They firstly used diethyl maleate 55 as starting material, which was converted with TosMIC 16 into the 3,4-dicarbethoxy-substituted pyrrole 56. Then, after a series of reactions on the substituents, pyrrole carboxamide compound 57 was synthesized (Scheme 15) [35].

Alkenes with an Amide Group
Donohoe and co-workers continued to expand the reaction to TosMIC 16 with acrylic acid pyrrolidide 58 to generate two pyrroles in reasonable yields in 1998.

Alkenes with an Amide Group
Donohoe and co-workers continued to expand the reaction to TosMIC 16 with acrylic acid pyrrolidide 58 to generate two pyrroles in reasonable yields in 1998. The compound was subsequently protected under standard conditions to yield the N-Boc pyrrole 60. Under the similar conditions, N-Adoc pyrrole 61 could be obtained from cyclohexyl acrylate 59 and TosMIC 16, respectively (Scheme 16) [36].

Alkenes with an Amide Group
Donohoe and co-workers continued to expand the reaction to TosMIC 16 with acrylic acid pyrrolidide 58 to generate two pyrroles in reasonable yields in 1998.

Alkenes with an Amide Group
Donohoe and co-workers continued to expand the reaction to TosMIC 16 with acrylic acid pyrrolidide 58 to generate two pyrroles in reasonable yields in 1998.

Alkenes with a Keto Group
In 2000, Dannhardt and co-workers reported that 1,3-diarylprop-2-en-1-ones 70 and TosMIC 16 were dissolved in THF as solvent to produce 3-aroyl-4-arylpyrroles 71 in the presence of NaH at room temperature for 0.5 h. Then compounds 71 were alkylated at the pyrrole nitrogen to afford an Nsubstituted aryl-aroyl-pyrroles 72 (Scheme 19) [39].   In the same year, Terzidis et al. reported that chromone-3-carboxaldehydes 75 were allowed to react with equimolar amounts of TosMIC 16 in the presence of DBU, in the aprotic nonpolar solvent THF at room temperature. As a result 2-tosyl-4-(2-hydroxybenzoyl)pyrroles 76 were isolated in good yield (Scheme 21) [41]. In the following year, Ji et al. also discovered a method for synthesizing bridged 3,3 -dipyrrole derivatives 85 by the reaction of dienone derivatives 84 with TosMIC 16. In addition to the classical [3+2] cycloaddition reaction, this reaction also involves C-C bond cleavage caused by traces of water in the system. They also captured a spirocyclic intermediate, which is providing a new idea for the study of the construction of bispirocyclic compounds by isonitrile (Scheme 25) [45]. Solvation or dynamic solvent effects can affect the rate of [3+2] cycloaddition reaction between TosMIC and aromatic ketones. In 2013, Nair's group discovered a lithium hydroxide mediated 3,4disubstituted pyrrole synthesis method [49]. As shown in Scheme 29, acetophenone 94 was reacted Solvation or dynamic solvent effects can affect the rate of [3+2] cycloaddition reaction between TosMIC and aromatic ketones. In 2013, Nair's group discovered a lithium hydroxide mediated 3,4disubstituted pyrrole synthesis method [49]. As shown in Scheme 29, acetophenone 94 was reacted Solvation or dynamic solvent effects can affect the rate of [3+2] cycloaddition reaction between TosMIC and aromatic ketones. In 2013, Nair's group discovered a lithium hydroxide mediated 3,4disubstituted pyrrole synthesis method [49]. As shown in Scheme 29, acetophenone 94 was reacted Solvation or dynamic solvent effects can affect the rate of [3+2] cycloaddition reaction between TosMIC and aromatic ketones. In 2013, Nair's group discovered a lithium hydroxide mediated 3,4disubstituted pyrrole synthesis method [49]. As shown in Scheme 29, acetophenone 94 was reacted Solvation or dynamic solvent effects can affect the rate of [3+2] cycloaddition reaction between TosMIC and aromatic ketones. In 2013, Nair's group discovered a lithium hydroxide mediated 3,4-disubstituted pyrrole synthesis method [49]. As shown in Scheme 29, acetophenone 94 was reacted with benzaldehyde 95 in the presence of LiOH·H 2 O in ethanol medium to afford 1,3-diphenylprop-2-enone 96 by an aldol condensation between the enolate and the electrophile. Then, TosMIC 16 and an additional equivalent of LiOH·H 2 O were added to the same system. As the reaction progressed, a white solid precipitated from the reaction medium, the product obtained was filtered, washed with water and ethanol, and characterized as phenyl(4-phenyl-1H-pyrrol-3-yl)methanone 97. In this reaction system, due to the small size of Li + ion, LiOH·H 2 O has obvious covalent character, which slows down the release of OH -. At the same time, a solvation effect occurs in the polar solvent to increase the yield.
A plausible mechanism for the reaction is depicted in Scheme 30. with benzaldehyde 95 in the presence of LiOH·H2O in ethanol medium to afford 1,3-diphenylprop-2-enone 96 by an aldol condensation between the enolate and the electrophile. Then, TosMIC 16 and an additional equivalent of LiOH·H2O were added to the same system. As the reaction progressed, a white solid precipitated from the reaction medium, the product obtained was filtered, washed with water and ethanol, and characterized as phenyl(4-phenyl-1Hpyrrol-3-yl)methanone 97. In this reaction system, due to the small size of Li + ion, LiOH·H2O has obvious covalent character, which slows down the release of OH -. At the same time, a solvation effect occurs in the polar solvent to increase the yield.
A plausible mechanism for the reaction is depicted in Scheme 30. LiOH·H2O abstracts a proton from the methylene group of TosMIC to generate a carbanion which can be stabilized by the sulfonyl group. In 2016, Nair and co-workers also reported an aroyl-substituted pyrroles 105 synthetic route from phosphonium salt 102 as starting material. The phosphonium salt was neutralized with aqueous NaOH and extracted with dichloromethane to afford 1-phenyl-2-(triphenylphosphoranylidene)ethenone 103. Further the compound was reacted with isobutyraldehyde in dichloromethane to generate the corresponding α,β-unsaturated ketone 104. Upon completion of the reaction, dichloromethane was evaporated and the reaction mixture was triturated with hexane to remove triphenylphosphine oxide. Moreover, they found that LiOH·H2O gave good yields of the desired product as compared to NaOH and KOH. This might be due to better coordination power of lithium (Scheme 31) [50]. with benzaldehyde 95 in the presence of LiOH·H2O in ethanol medium to afford 1,3-diphenylprop-2-enone 96 by an aldol condensation between the enolate and the electrophile. Then, TosMIC 16 and an additional equivalent of LiOH·H2O were added to the same system. As the reaction progressed, a white solid precipitated from the reaction medium, the product obtained was filtered, washed with water and ethanol, and characterized as phenyl(4-phenyl-1Hpyrrol-3-yl)methanone 97. In this reaction system, due to the small size of Li + ion, LiOH·H2O has obvious covalent character, which slows down the release of OH -. At the same time, a solvation effect occurs in the polar solvent to increase the yield.
A plausible mechanism for the reaction is depicted in Scheme 30. LiOH·H2O abstracts a proton from the methylene group of TosMIC to generate a carbanion which can be stabilized by the sulfonyl group. In 2016, Nair and co-workers also reported an aroyl-substituted pyrroles 105 synthetic route from phosphonium salt 102 as starting material. The phosphonium salt was neutralized with aqueous NaOH and extracted with dichloromethane to afford 1-phenyl-2-(triphenylphosphoranylidene)ethenone 103. Further the compound was reacted with isobutyraldehyde in dichloromethane to generate the corresponding α,β-unsaturated ketone 104. Upon completion of the reaction, dichloromethane was evaporated and the reaction mixture was triturated with hexane to remove triphenylphosphine oxide. Moreover, they found that LiOH·H2O gave good yields of the desired product as compared to NaOH and KOH. This might be due to better coordination power of lithium (Scheme 31) [50]. In 2016, Nair and co-workers also reported an aroyl-substituted pyrroles 105 synthetic route from phosphonium salt 102 as starting material. The phosphonium salt was neutralized with aqueous NaOH and extracted with dichloromethane to afford 1-phenyl-2-(triphenyl-phosphoranylidene)ethenone 103. Further the compound was reacted with isobutyraldehyde in dichloromethane to generate the corresponding α,β-unsaturated ketone 104. Upon completion of the reaction, dichloromethane was evaporated and the reaction mixture was triturated with hexane to remove triphenylphosphine oxide. Moreover, they found that LiOH·H 2 O gave good yields of the desired product as compared to NaOH and KOH. This might be due to better coordination power of lithium (Scheme 31) [50]. with benzaldehyde 95 in the presence of LiOH·H2O in ethanol medium to afford 1,3-diphenylprop-2-enone 96 by an aldol condensation between the enolate and the electrophile. Then, TosMIC 16 and an additional equivalent of LiOH·H2O were added to the same system. As the reaction progressed, a white solid precipitated from the reaction medium, the product obtained was filtered, washed with water and ethanol, and characterized as phenyl(4-phenyl-1Hpyrrol-3-yl)methanone 97. In this reaction system, due to the small size of Li + ion, LiOH·H2O has obvious covalent character, which slows down the release of OH -. At the same time, a solvation effect occurs in the polar solvent to increase the yield.
A plausible mechanism for the reaction is depicted in Scheme 30. LiOH·H2O abstracts a proton from the methylene group of TosMIC to generate a carbanion which can be stabilized by the sulfonyl group. In 2016, Nair and co-workers also reported an aroyl-substituted pyrroles 105 synthetic route from phosphonium salt 102 as starting material. The phosphonium salt was neutralized with aqueous NaOH and extracted with dichloromethane to afford 1-phenyl-2-(triphenylphosphoranylidene)ethenone 103. Further the compound was reacted with isobutyraldehyde in dichloromethane to generate the corresponding α,β-unsaturated ketone 104. Upon completion of the reaction, dichloromethane was evaporated and the reaction mixture was triturated with hexane to remove triphenylphosphine oxide. Moreover, they found that LiOH·H2O gave good yields of the desired product as compared to NaOH and KOH. This might be due to better coordination power of lithium (Scheme 31) [50]. Multi-component Van Leusen pyrrole synthesis can also occur in alkenes with aromatic ketones. In 2014, the Shanmugam research group found that cinnamoylketene dithioacetal 106 undergo multi-component cycloaddition with TosMIC 16, guanidine nitrate 107 and alkyl alcohol 108 in the presence of NaH/THF to furnish the target 6-pyrrolylpyrimidines 109 in excellent yields of 70-97% (Scheme 32) [51]. Because of the electron donating characteristics of the two methyl sulfanyl groups and the structural features of α,β-unsaturated carbonyl group, the arylvinyl double bond is more polarized than the ketene acetal double bond, which causes TosMIC 16 to selectively react at the arylvinyl double bond.
Molecules 2018, 23, x FOR PEER REVIEW 13 of 19 32) [51]. Because of the electron donating characteristics of the two methyl sulfanyl groups and the structural features of α,β-unsaturated carbonyl group, the arylvinyl double bond is more polarized than the ketene acetal double bond, which causes TosMIC 16 to selectively react at the arylvinyl double bond.

Alkenes with a Nitro Group
In 2009, Xiaoqi Yu and co-workers reported that 4(3)-substituted 3(4)-nitro-1H-pyrrole 111 can be synthesized from nitroene 110 and TosMIC 16 in the presence of the ionic liquid 1-butyl-3methylimidazolium bromide ([bmIm]Br). This reaction can be widely applied to aromatic, aliphatic or heterocyclic substituted nitroolefins, and the recovered ionic liquid can be repeatedly used as a solvent without significantly reducing the yield (Scheme 33) [52].

Alkenes with a Cyano Group
In 2012, the Yongping Yu group reported that two equivalents of a cyano-substituted trisubstituted alkene 112 and TosMIC 16 were dissolved in anhydrous acetonitrile as a solvent and reacted in the presence of NaH at room temperature for 3 h to form disubstituted pyrrole derivatives 113. And the 1,3'-bipyrrole 114 is obtained if the reaction time is extended to 12 h (Scheme 34) [53,54].
In the experiments, researchers also found that when keto and ester groups are simultaneously present in alkenes, due to the higher reactivity, keto group can be eliminated more easily than ester groups alone. In addition, group with larger steric hindrance can reduce the reactivity when they are present on alkenes.

Alkenes with a Nitro Group
In 2009, Xiaoqi Yu and co-workers reported that 4(3)-substituted 3(4)-nitro-1H-pyrrole 111 can be synthesized from nitroene 110 and TosMIC 16 in the presence of the ionic liquid 1-butyl-3-methylimidazolium bromide ([bmIm]Br). This reaction can be widely applied to aromatic, aliphatic or heterocyclic substituted nitroolefins, and the recovered ionic liquid can be repeatedly used as a solvent without significantly reducing the yield (Scheme 33) [52]. 32) [51]. Because of the electron donating characteristics of the two methyl sulfanyl groups and the structural features of α,β-unsaturated carbonyl group, the arylvinyl double bond is more polarized than the ketene acetal double bond, which causes TosMIC 16 to selectively react at the arylvinyl double bond.

Alkenes with a Nitro Group
In 2009, Xiaoqi Yu and co-workers reported that 4(3)-substituted 3(4)-nitro-1H-pyrrole 111 can be synthesized from nitroene 110 and TosMIC 16 in the presence of the ionic liquid 1-butyl-3methylimidazolium bromide ([bmIm]Br). This reaction can be widely applied to aromatic, aliphatic or heterocyclic substituted nitroolefins, and the recovered ionic liquid can be repeatedly used as a solvent without significantly reducing the yield (Scheme 33) [52].

Alkenes with a Cyano Group
In 2012, the Yongping Yu group reported that two equivalents of a cyano-substituted trisubstituted alkene 112 and TosMIC 16 were dissolved in anhydrous acetonitrile as a solvent and reacted in the presence of NaH at room temperature for 3 h to form disubstituted pyrrole derivatives 113. And the 1,3'-bipyrrole 114 is obtained if the reaction time is extended to 12 h (Scheme 34) [53,54].
In the experiments, researchers also found that when keto and ester groups are simultaneously present in alkenes, due to the higher reactivity, keto group can be eliminated more easily than ester groups alone. In addition, group with larger steric hindrance can reduce the reactivity when they are present on alkenes.

Alkenes with a Cyano Group
In 2012, the Yongping Yu group reported that two equivalents of a cyano-substituted trisubstituted alkene 112 and TosMIC 16 were dissolved in anhydrous acetonitrile as a solvent and reacted in the presence of NaH at room temperature for 3 h to form disubstituted pyrrole derivatives 113. And the 1,3'-bipyrrole 114 is obtained if the reaction time is extended to 12 h (Scheme 34) [53,54]. In the experiments, researchers also found that when keto and ester groups are simultaneously present in alkenes, due to the higher reactivity, keto group can be eliminated more easily than ester groups alone. In addition, group with larger steric hindrance can reduce the reactivity when they are present on alkenes.

Alkenes with a Nitro Group
In 2009, Xiaoqi Yu and co-workers reported that 4(3)-substituted 3(4)-nitro-1H-pyrrole 111 can be synthesized from nitroene 110 and TosMIC 16 in the presence of the ionic liquid 1-butyl-3methylimidazolium bromide ([bmIm]Br). This reaction can be widely applied to aromatic, aliphatic or heterocyclic substituted nitroolefins, and the recovered ionic liquid can be repeatedly used as a solvent without significantly reducing the yield (Scheme 33) [52].

Alkenes with a Cyano Group
In 2012, the Yongping Yu group reported that two equivalents of a cyano-substituted trisubstituted alkene 112 and TosMIC 16 were dissolved in anhydrous acetonitrile as a solvent and reacted in the presence of NaH at room temperature for 3 h to form disubstituted pyrrole derivatives 113. And the 1,3'-bipyrrole 114 is obtained if the reaction time is extended to 12 h (Scheme 34) [53,54].
In the experiments, researchers also found that when keto and ester groups are simultaneously present in alkenes, due to the higher reactivity, keto group can be eliminated more easily than ester groups alone. In addition, group with larger steric hindrance can reduce the reactivity when they are present on alkenes.

Alkenes with an Aryl Group
In 2002, Smith and co-workers developed a method for the one-step synthesis of 3-aryl and 3,4-diarylpyrroles 116 with good yields by readily available aryl or diaryl alkenes 115 with TosMIC 16 (Scheme 35) [55]. They found that the stronger the electron-withdrawing ability of the aryl group attached to the alkene in the substrate, the lower the temperature required for the reaction, the shorter the reaction time, and the higher yield. At the same time, the steric hindrance of the aryl group will act as a deterrent to the reaction. This phenomenon is particularly evident when the aryl group is ortho-substituted.

Alkenes with an Aryl Group
In 2002, Smith and co-workers developed a method for the one-step synthesis of 3-aryl and 3,4diarylpyrroles 116 with good yields by readily available aryl or diaryl alkenes 115 with TosMIC 16 (Scheme 35) [55]. They found that the stronger the electron-withdrawing ability of the aryl group attached to the alkene in the substrate, the lower the temperature required for the reaction, the shorter the reaction time, and the higher yield. At the same time, the steric hindrance of the aryl group will act as a deterrent to the reaction. This phenomenon is particularly evident when the aryl group is ortho-substituted.

Alkenes with an Aryl Group
In 2002, Smith and co-workers developed a method for the one-step synthesis of 3-aryl and 3,4diarylpyrroles 116 with good yields by readily available aryl or diaryl alkenes 115 with TosMIC 16 (Scheme 35) [55]. They found that the stronger the electron-withdrawing ability of the aryl group attached to the alkene in the substrate, the lower the temperature required for the reaction, the shorter the reaction time, and the higher yield. At the same time, the steric hindrance of the aryl group will act as a deterrent to the reaction. This phenomenon is particularly evident when the aryl group is ortho-substituted.

Alkenes with an Aryl Group
In 2002, Smith and co-workers developed a method for the one-step synthesis of 3-aryl and 3,4diarylpyrroles 116 with good yields by readily available aryl or diaryl alkenes 115 with TosMIC 16 (Scheme 35) [55]. They found that the stronger the electron-withdrawing ability of the aryl group attached to the alkene in the substrate, the lower the temperature required for the reaction, the shorter the reaction time, and the higher yield. At the same time, the steric hindrance of the aryl group will act as a deterrent to the reaction. This phenomenon is particularly evident when the aryl group is ortho-substituted. In 2012, Yongping Yu and co-workers reported synthesis of polysubstituted pyrroles 126 from TosMIC 16 and vinyl azides 125 under mild conditions in the presence of base (Scheme 38) [59]. Additionally, they developed a Van Leusen three-component reaction as a synthesis of 2,3,4-trisubstituted pyrrole 129, where a mixture of 3-nitrobenzaldehyde 127 and ethyl 2-azidoacetate 128 was stirred under the Knoevenagel condensation conditions using NaH as the base for 2 h at −15 • C, followed by addition of TosMIC 16. The reaction mixture was then stirred at room temperature for 24 h to give the desired product 129 (Scheme 39) [59]. In 2017, our research group discovered that TosMIC 16 can undergo a [3+2] cycloaddition reaction with a styrylisoxazole compounds 130 to construct a series of 3-isoxazole disubstituted pyrrole derivatives 131 (Scheme 40) [60]. Under the same optimized reaction condition, the synthesis of the 3-isoxazole trisubstituted pyrrole derivatives 132 was achieved by using the TosMIC derivatives 16 (Scheme 41) [60]. This transformation is operationally simple, high-yielding, and displays broad substrate scope.

Synthesis of Pyrrole Derivatives by [3+2] Cycloaddition of TosMICs with Alkynes
Similar to alkenes, alkynes can also undergo [3+2] cycloaddition with TosMIC to synthesize pyrrole derivatives. As early as in 1979, Saikachi and co-workers found that acetylene ester 133 (2 equiv each) and TosMIC 16 can produce 2,3,4-trisubstituted pyrrole compounds 134 in the presence of DBU. The 1,2,3,4-tetrasubstituted pyrrole compounds 135 can be synthesized by another one-step addition reaction (Scheme 42) [61]. In 2011, the Adib group developed a protocol that is different with respect to the common shortcomings such as long reaction time, low yield, expensive raw materials, and harsh reaction conditions. A mixture of TosMIC 16, and a dialkyl acetylenedicarboxylate 138, in the presence of a catalytic amount of 1-methylimidazole 139 undergoes a smooth addition reaction in anhydrous CH2Cl2 at room temperature to afford 2,3,4-trisubstituted pyrroles 140 in yields of 90-95% (Scheme 44) [63].

Conclusions
In summary, the Van Leusen [3+2] cycloaddition reaction based on TosMICs and electrondeficient compounds is involved in the construction of pyrrole and its derivatives because of its advantages such as simple and convenient synthesis substrate, diverse products, etc., and will play an increasingly important role in the synthesis of bioactive pyrrole derivatives in the pharmaceutical synthesis. In recent years, some research progress has been made, which provides new ideas for the synthesis of polysubstituted pyrrole ring framework. In the future, there will be a focus on developing more types and higher selectivity 2-carbon synthons in subsequent research to increase the expansion of the reaction.
Author Contributions: All authors wrote the paper. All authors read and approved the final manuscript.
Funding: Financial support of this research provided by Science and Technology Planning Project of Jilin Province (20160414015GH) is greatly acknowledged.

Conflicts of Interest:
The authors declare no conflict of interest. In this reaction, the nucleophilic addition of Ph 3 P to the acetylenic esters further increases the reactivity of the substrate as an electron-withdrawing group (Scheme 43) [62]. In 2011, the Adib group developed a protocol that is different with respect to the common shortcomings such as long reaction time, low yield, expensive raw materials, and harsh reaction conditions. A mixture of TosMIC 16, and a dialkyl acetylenedicarboxylate 138, in the presence of a catalytic amount of 1-methylimidazole 139 undergoes a smooth addition reaction in anhydrous CH2Cl2 at room temperature to afford 2,3,4-trisubstituted pyrroles 140 in yields of 90-95% (Scheme 44) [63].

Conclusions
In summary, the Van Leusen [3+2] cycloaddition reaction based on TosMICs and electrondeficient compounds is involved in the construction of pyrrole and its derivatives because of its advantages such as simple and convenient synthesis substrate, diverse products, etc., and will play an increasingly important role in the synthesis of bioactive pyrrole derivatives in the pharmaceutical synthesis. In recent years, some research progress has been made, which provides new ideas for the synthesis of polysubstituted pyrrole ring framework. In the future, there will be a focus on developing more types and higher selectivity 2-carbon synthons in subsequent research to increase the expansion of the reaction.
Author Contributions: All authors wrote the paper. All authors read and approved the final manuscript.
Funding: Financial support of this research provided by Science and Technology Planning Project of Jilin Province (20160414015GH) is greatly acknowledged.

Conflicts of Interest:
The authors declare no conflict of interest. In 2011, the Adib group developed a protocol that is different with respect to the common shortcomings such as long reaction time, low yield, expensive raw materials, and harsh reaction conditions. A mixture of TosMIC 16, and a dialkyl acetylenedicarboxylate 138, in the presence of a catalytic amount of 1-methylimidazole 139 undergoes a smooth addition reaction in anhydrous CH 2 Cl 2 at room temperature to afford 2,3,4-trisubstituted pyrroles 140 in yields of 90-95% (Scheme 44) [63]. In 2011, the Adib group developed a protocol that is different with respect to the common shortcomings such as long reaction time, low yield, expensive raw materials, and harsh reaction conditions. A mixture of TosMIC 16, and a dialkyl acetylenedicarboxylate 138, in the presence of a catalytic amount of 1-methylimidazole 139 undergoes a smooth addition reaction in anhydrous CH2Cl2 at room temperature to afford 2,3,4-trisubstituted pyrroles 140 in yields of 90-95% (Scheme 44) [63].

Conclusions
In summary, the Van Leusen [3+2] cycloaddition reaction based on TosMICs and electrondeficient compounds is involved in the construction of pyrrole and its derivatives because of its advantages such as simple and convenient synthesis substrate, diverse products, etc., and will play an increasingly important role in the synthesis of bioactive pyrrole derivatives in the pharmaceutical synthesis. In recent years, some research progress has been made, which provides new ideas for the synthesis of polysubstituted pyrrole ring framework. In the future, there will be a focus on developing more types and higher selectivity 2-carbon synthons in subsequent research to increase the expansion of the reaction.
Author Contributions: All authors wrote the paper. All authors read and approved the final manuscript.

Conclusions
In summary, the Van Leusen [3+2] cycloaddition reaction based on TosMICs and electron-deficient compounds is involved in the construction of pyrrole and its derivatives because of its advantages such as simple and convenient synthesis substrate, diverse products, etc., and will play an increasingly important role in the synthesis of bioactive pyrrole derivatives in the pharmaceutical synthesis. In recent years, some research progress has been made, which provides new ideas for the synthesis of polysubstituted pyrrole ring framework. In the future, there will be a focus on developing more types and higher selectivity 2-carbon synthons in subsequent research to increase the expansion of the reaction.