Recent Trends in the Petasis Reaction: A Review of Novel Catalytic Synthetic Approaches with Applications of the Petasis Reaction

The Petasis reaction, also called the Petasis Borono–Mannich reaction, is a multicomponent reaction that couples a carbonyl derivative, an amine and boronic acids to yield substituted amines. The reaction proceeds efficiently in the presence or absence of a specific catalyst and solvent. By employing this reaction, a diverse range of chiral derivatives can easily be obtained, including α-amino acids. A broad substrate scope, high yields, distinct functional group tolerance and the availability of diverse catalytic systems constitute key features of this reaction. In this review article, attention has been drawn toward the recently reported methodologies for executing the Petasis reaction to produce structurally simple to complex aryl/allyl amino scaffolds.


Introduction
Multicomponent reactions constitute the coupling between more than two components which are incorporated into the final product [1].A number of advantages are accredited to this type of reaction.These include atom economy, as the majority of reactants become part of the product; efficiency, because of high product yield; convergence; and exhibiting a high index of bond formation.Some of the important multicomponent reactions are Ugi, Strecker, Passerini, Hantzch, Betti and Biginelli reactions [2][3][4][5][6].Multicomponent reactions find their applications in the stereoselective transformations including the synthesis/reactions of heterocycles such as pyrazines, epoxides and aziridines [7][8][9][10].These reactions have been widely employed in medicinal and combinatorial chemistry for purposes of the drugdiscovery process to construct biologically active scaffolds [11].
The Petasis reaction is one of the significant multicomponent reactions [12].It takes place between an amine, a carbonyl group and boronic acids.This reaction provides highly stereoselective products under facile reaction conditions (short duration and mild temperature), providing access to a wide range of substrates.It can proceed either via nanoparticles, Lewis acids, metal catalysts or catalyst-free conditions with minimal requirement of protecting groups [13][14][15].It was first reported by Petasis and his coworkers in 1993, who obtained allyl amines, i.e., naftifine, an anti-fungal agent from paraformaldehyde, secondary amine and E-vinyl boronic acid, constituting an archetype of the Petasis reaction [16].The other transformations of the Petasis reaction involved Petasis-olefination, which is the dimethyl titanocene-mediated olefination of ketone or aldehyde and the Petasis-Ferrier reaction which is the formation of tetrahydrofuran from cyclic acetals.It has evolved into a highly functionalized multicomponent reaction, with a lot of key features.A general reaction scheme of Petasis reaction is presented in Figure 1 as follows [17]: scaffolds [11].
The Petasis reaction is one of the significant multicomponent reactions [12].It t place between an amine, a carbonyl group and boronic acids.This reaction prov highly stereoselective products under facile reaction conditions (short duration and m temperature), providing access to a wide range of substrates.It can proceed either nanoparticles, Lewis acids, metal catalysts or catalyst-free conditions with minima quirement of protecting groups [13][14][15].It was first reported by Petasis and his cowor in 1993, who obtained allyl amines, i.e., naftifine, an anti-fungal agent from parafor dehyde, secondary amine and E-vinyl boronic acid, constituting an archetype of Petasis reaction [16].The other transformations of the Petasis reaction involved P sis-olefination, which is the dimethyl titanocene-mediated olefination of ketone o dehyde and the Petasis-Ferrier reaction which is the formation of tetrahydrofuran f cyclic acetals.It has evolved into a highly functionalized multicomponent reaction, w lot of key features.A general reaction scheme of Petasis reaction is presented in Figu as follows [17]: Focusing on the applications of this reaction, a variety of lead compounds with nificant biological potential have been constructed, such as naftifine, which is an ac antifungal compound.In addition to this, the synthesis of (−)-clavosolide A (−)-okilactomycin 2, (−)-kendomycin 3 and (+)-phorboxazole A 4 was also accomplis via this reaction.The Petasis-Ferrier reaction played an important role in the total thesis of (−)-clavosolide A 1 [18].The (−)-okilactomycin 2 has been reported to be a nificant cytotoxic compound with an IC50 value of 0.037 and 0.09 µ g/mL against phoid leukemia and cell line P388, respectively [19].The Petasis-Ferrier reaction is on the many steps in the total synthesis of (−)-kendomycin 3 and (+)-phorboxazole [20,21].Figure 2 contains the structures of the above-mentioned compounds.Focusing on the applications of this reaction, a variety of lead compounds with significant biological potential have been constructed, such as naftifine, which is an active antifungal compound.In addition to this, the synthesis of (−)-clavosolide A 1, (−)-okilactomycin 2, (−)-kendomycin 3 and (+)-phorboxazole A 4 was also accomplished via this reaction.The Petasis-Ferrier reaction played an important role in the total synthesis of (−)-clavosolide A 1 [18].The (−)-okilactomycin 2 has been reported to be a significant cytotoxic compound with an IC 50 value of 0.037 and 0.09 µg/mL against lymphoid leukemia and cell line P388, respectively [19].The Petasis-Ferrier reaction is one of the many steps in the total synthesis of (−)-kendomycin 3 and (+)-phorboxazole A 4 [20,21].Figure 2 contains the structures of the above-mentioned compounds.
The Petasis reaction provides a powerful route to access tertiary amines, amino esters, allenes, amino acids, functionalized γ-lactams, 2-aminothiophenes and thienodiazepines, and many reports regarding this reaction have been published during the last few years [22][23][24][25][26][27][28].The contents of this review have been divided based on different conditions employed for Petasis reactions (such as Petasis reactions catalyzed by nanoparticles, chiral catalysts, acid-catalyzed reactions, catalyst-free reactions, solvent-free reactions, base-catalyzed reactions and miscellaneous reactions) reported in recent years.The Petasis reaction provides a powerful route to access tertiary amines, amino esters, allenes, amino acids, functionalized γ-lactams, 2-aminothiophenes and thienodiazepines, and many reports regarding this reaction have been published during the last few years [22][23][24][25][26][27][28].The contents of this review have been divided based on different conditions employed for Petasis reactions (such as Petasis reactions catalyzed by nanoparticles, chiral catalysts, acid-catalyzed reactions, catalyst-free reactions, solvent-free reactions, base-catalyzed reactions and miscellaneous reactions) reported in recent years.

Petasis Reaction Catalyzed by Nanoparticles
Alkylaminophenols are a part of different pharmacological drugs, e.g., amodiaquine and topotecan [29,30].Although the first synthesis of these compounds was catalyst-free, affording a low yield range [31], keeping those considerations in mind, Kulkarni et al. reported in 2015 for the first time, the catalyst-based Petasis borono-Mannich reaction to achieve alkylaminophenols (72-93%).They examined the effect of spinel ferrites as catalysts (Fe3O4, NiFe2O4, CoFe2O4 and CuFe2O4) in the synthesis of alkylaminophenols at different temperatures and times.Consequently, CoFe2O4 was found to be the most suitable catalyst for the reaction due to its ease of separation by an external magnet.After the optimization of reaction conditions (15 mol% CoFe2O4, CH3CN, 80 °C) the effect of electron-donating and electron-withdrawing substituents on salicylaldehyde and aryl boronic acid was evaluated.In that respect, salicylaldehydes with substitutions (5-Br, 3,5-Br, 4-OMe and 5-Cl); different amines, i.e., piperazine, morpholine, pyrrolidine and N-dibenzylmethyl amine; and boronic acids with substitutions (4-tBu, 4-Cl, 4-OMe,

Petasis Reaction Catalyzed by Nanoparticles
Alkylaminophenols are a part of different pharmacological drugs, e.g., amodiaquine and topotecan [29,30].Although the first synthesis of these compounds was catalyst-free, affording a low yield range [31], keeping those considerations in mind, Kulkarni et al. reported in 2015 for the first time, the catalyst-based Petasis borono-Mannich reaction to achieve alkylaminophenols (72-93%).They examined the effect of spinel ferrites as catalysts (Fe 3 O 4 , NiFe 2 O 4 , CoFe 2 O 4 and CuFe 2 O 4 ) in the synthesis of alkylaminophenols at different temperatures and times.Consequently, CoFe 2 O 4 was found to be the most suitable catalyst for the reaction due to its ease of separation by an external magnet.After the optimization of reaction conditions (15 mol% CoFe 2 O 4 , CH 3 CN, 80 • C) the effect of electron-donating and electron-withdrawing substituents on salicylaldehyde and aryl boronic acid was evaluated.In that respect, salicylaldehydes with substitutions (5-Br, 3,5-Br, 4-OMe and 5-Cl); different amines, i.e., piperazine, morpholine, pyrrolidine and N-dibenzylmethyl amine; and boronic acids with substitutions (4-tBu, 4-Cl, 4-OMe, 3-NO 2 ) were employed to obtain 72-93% yields with 19 examples.A highlighted example is presented in Scheme 1.The best yield was obtained when salicylaldehyde 5 and piperidine 6 were treated with t-butylphenylboronic acid 7 using a CoFe 2 O 4 catalyst in acetonitrile at 80 • C to afford alkylaminophenol 8 in 93% yield.Some significant attributes of this reaction are benign rection conditions, moderate to high yields and the short duration required for reaction completion [32].
3-NO2) were employed to obtain 72-93% yields with 19 examples.A highlighted example is presented in Scheme 1.The best yield was obtained when salicylaldehyde 5 and piperidine 6 were treated with t-butylphenylboronic acid 7 using a CoFe2O4 catalyst in acetonitrile at 80 °C to afford alkylaminophenol 8 in 93% yield.Some significant attributes of this reaction are benign rection conditions, moderate to high yields and the short duration required for reaction completion [32].Recently, Rafiee and Hosseinvand reported the synthesis of a nanocomposite composed of graphene oxide modified with N-amidinoglycine having immobilized copper ions.This nanocomposite was efficiently utilized in a Petasis-Borono Mannich reaction to synthesize aminophenol 10 with 100% conversion in a solvent-free environment via Fe3O4@GO@AG@Cu II catalysis, as presented in Scheme 2 [33].The substrate scope of this methodology includes the employment of salicylaldehydes with 3-OMe, 4-OMe and 5-Br substitutions; boronic acids with 3-Me, 3-OMe and 4-acyl; and an amine component, i.e., piperidine, morpholine and 2-methyl piperidine, to provide 65-100% conversion of reagents.The salient features of this methodology were excellent catalytic activity for five consecutive runs, best yields, brief reaction times and facile recovery.Magnetic nanoparticles, consisting of metals or their oxides, have received much attention in recent years owing to a number of mention-worthy properties, which include non-toxic nature, low cost, and oxidative stability, making them a good candidate for catalyzing several reactions, including the Petasis-Borono Mannich reaction.Shivashankar and Chacko synthesized novel aminomethylphenols bearing a piperidine moiety (80-94%) by using a catalytic amount of magnetic Fe3O4 nanoparticles.For that purpose, several substituted salicylaldehydes with 5-Br, 5-NO2, 5-OMe and 5-Me substitutions were reacted with boronic acids having 4-Cl and 4-Br substitution and substituted imidazole and indole to furnish 80-94% yields of target compounds.The best results were obtained when 2-hydroxy-5-methoxybenzaldehyde 11 was allowed to react with Recently, Rafiee and Hosseinvand reported the synthesis of a nanocomposite composed of graphene oxide modified with N-amidinoglycine having immobilized copper ions.This nanocomposite was efficiently utilized in a Petasis-Borono Mannich reaction to synthesize aminophenol 10 with 100% conversion in a solvent-free environment via Fe 3 O 4 @GO@AG@Cu II catalysis, as presented in Scheme 2 [33].The substrate scope of this methodology includes the employment of salicylaldehydes with 3-OMe, 4-OMe and 5-Br substitutions; boronic acids with 3-Me, 3-OMe and 4-acyl; and an amine component, i.e., piperidine, morpholine and 2-methyl piperidine, to provide 65-100% conversion of reagents.The salient features of this methodology were excellent catalytic activity for five consecutive runs, best yields, brief reaction times and facile recovery.
of this reaction are benign rection conditions, moderate to high yields and the short duration required for reaction completion [32].Recently, Rafiee and Hosseinvand reported the synthesis of a nanocomposite composed of graphene oxide modified with N-amidinoglycine having immobilized copper ions.This nanocomposite was efficiently utilized in a Petasis-Borono Mannich reaction to synthesize aminophenol 10 with 100% conversion in a solvent-free environment via Fe3O4@GO@AG@Cu II catalysis, as presented in Scheme 2 [33].The substrate scope of this methodology includes the employment of salicylaldehydes with 3-OMe, 4-OMe and 5-Br substitutions; boronic acids with 3-Me, 3-OMe and 4-acyl; and an amine component, i.e., piperidine, morpholine and 2-methyl piperidine, to provide 65-100% conversion of reagents.The salient features of this methodology were excellent catalytic activity for five consecutive runs, best yields, brief reaction times and facile recovery.Magnetic nanoparticles, consisting of metals or their oxides, have received much attention in recent years owing to a number of mention-worthy properties, which include non-toxic nature, low cost, and oxidative stability, making them a good candidate for catalyzing several reactions, including the Petasis-Borono Mannich reaction.Shivashankar and Chacko synthesized novel aminomethylphenols bearing a piperidine moiety (80-94%) by using a catalytic amount of magnetic Fe3O4 nanoparticles.For that purpose, several substituted salicylaldehydes with 5-Br, 5-NO2, 5-OMe and 5-Me substitutions were reacted with boronic acids having 4-Cl and 4-Br substitution and substituted imidazole and indole to furnish 80-94% yields of target compounds.The best results were obtained when 2-hydroxy-5-methoxybenzaldehyde 11 was allowed to react with Scheme 2. Synthetic approach for aminophenol 10.
Magnetic nanoparticles, consisting of metals or their oxides, have received much attention in recent years owing to a number of mention-worthy properties, which include non-toxic nature, low cost, and oxidative stability, making them a good candidate for catalyzing several reactions, including the Petasis-Borono Mannich reaction.Shivashankar and Chacko synthesized novel aminomethylphenols bearing a piperidine moiety (80-94%) by using a catalytic amount of magnetic Fe 3 O 4 nanoparticles.For that purpose, several substituted salicylaldehydes with 5-Br, 5-NO 2 , 5-OMe and 5-Me substitutions were reacted with boronic acids having 4-Cl and 4-Br substitution and substituted imidazole and indole to furnish 80-94% yields of target compounds.The best results were obtained when 2hydroxy-5-methoxybenzaldehyde 11 was allowed to react with phenylboronic acid 9 and amine 12 to furnish aminomethylphenol 13 in 94% yield using 2 mol% of nano Fe 3 O 4 in dry dioxane at room temperature.The catalyst provided high yields of target compounds even with four consecutive reruns (Scheme 3) [34].
s 2023, 28, x FOR PEER REVIEW 5 of 21 phenylboronic acid 9 and amine 12 to furnish aminomethylphenol 13 in 94% yield using 2 mol% of nano Fe3O4 in dry dioxane at room temperature.The catalyst provided high yields of target compounds even with four consecutive reruns (Scheme 3) [34].

Petasis Reaction Involving Chiral Catalysts
The synthesis of chiral compounds and their utility has been a topic of discussion.For that purpose, chiral catalysts are employed.Han et al. synthesized alkylaminophenols (57-87% yield range and enantioselectivities 40-86% ee) via a Petasis reaction using chiral BINOL (1,1′-bi-2-naphthol) as a catalyst.Maximum yield was obtained by treating salicylaldehyde 5 with morpholine 14 and 4-methoxybenzoic acid 15 using chiral BINOL 16 (R) as a catalyst in mesitylene at 0 °C to obtain compound 17(R) in 87% yield with 53% ee (Scheme 4) [35].Besides that, substituted aldehydes bearing (5-NO2, 5-OMe and 5-Bz), diverse amine components (pyrrolidine and piperidine) and different boronic acids bearing (4-OMe, 4-OBn, 4-OMOM, 4-Cl) substitutions were also employed for this reaction.Thus, asymmetric synthesis with the BINOL catalyst exhibits a wide substrate scope and acceptable enantioselectivities. Considering the efficient activity of organocatalysts synthesized using a thiourea moiety in organic reactions, Han et al. treated a variety of salicylaldehydes with secondary amines and organoboronic acids to attain 48-92% yield range of the targeted compounds using a thiourea-derived catalyst.It was observed that 5-methoxy and 5-nitro Scheme 3. Synthesis of aminomethylphenol 13.
phenylboronic acid 9 and amine 12 to furnish aminomethylphenol 13 in 94% yield using 2 mol% of nano Fe3O4 in dry dioxane at room temperature.The catalyst provided high yields of target compounds even with four consecutive reruns (Scheme 3) [34].Scheme 3. Synthesis of aminomethylphenol 13.

Petasis Reaction Involving Chiral Catalysts
The synthesis of chiral compounds and their utility has been a topic of discussion.For that purpose, chiral catalysts are employed.Han et al. synthesized alkylaminophenols (57-87% yield range and enantioselectivities 40-86% ee) via a Petasis reaction using chiral BINOL (1,1′-bi-2-naphthol) as a catalyst.Maximum yield was obtained by treating salicylaldehyde 5 with morpholine 14 and 4-methoxybenzoic acid 15 using chiral BINOL 16 (R) as a catalyst in mesitylene at 0 °C to obtain compound 17(R) in 87% yield with 53% ee (Scheme 4) [35].Besides that, substituted aldehydes bearing (5-NO2, 5-OMe and 5-Bz), diverse amine components (pyrrolidine and piperidine) and different boronic acids bearing (4-OMe, 4-OBn, 4-OMOM, 4-Cl) substitutions were also employed for this reaction.Thus, asymmetric synthesis with the BINOL catalyst exhibits a wide substrate scope and acceptable enantioselectivities. Considering the efficient activity of organocatalysts synthesized using a thiourea moiety in organic reactions, Han et al. treated a variety of salicylaldehydes with secondary amines and organoboronic acids to attain 48-92% yield range of the targeted compounds using a thiourea-derived catalyst.It was observed that 5-methoxy and 5-nitro Considering the efficient activity of organocatalysts synthesized using a thiourea moiety in organic reactions, Han et al. treated a variety of salicylaldehydes with secondary amines and organoboronic acids to attain 48-92% yield range of the targeted compounds using a thiourea-derived catalyst.It was observed that 5-methoxy and 5-nitro substituted salicyladehydes; 4-OMe, 4-OBn, 4-OMOM and 4-Cl substituted boronic acids; and morpholine, piperidine, pyrrolidine and tetrahydroisoquinoline have been used in this approach efficiently.The excellent yield of alkylaminophenol 23(R) (92%) with 90% ee was obtained when salicylaldehyde 5 was treated with pyrrolidine 18 and 4-methoxybenzoic acid 15 using catalyst 19(R) in methyl t-butyl ether (MTBE) (Scheme 5) [36].
Owing to the synthetic importance of amino acids (which are the building blocks of various peptides) [37], Lou and Schaus described the synthetic pathway for different amino acids (71-94%) using (S)-VAPOL catalyst 24 in 3Å MS/toluene mixture.These chiral catalysts behave as efficient catalysts for obtaining asymmetric products without using chiral substrates.The best results were obtained when secondary benzyl amine 22 was treated with alkenyl boronate 21 and glyoxylate 23 to afford α-amino acid (R,E)-25 in 94% yield with 95:5 enantioselectivity (Scheme 6) [38].Moderate to good results were obtained when a number of substituted dibenzyl amines and boronates were employed.Owing to the synthetic importance of amino acids (which are the building blocks of various peptides) [37], Lou and Schaus described the synthetic pathway for different amino acids (71-94%) using (S)-VAPOL catalyst 24 in 3Å MS/toluene mixture.These chiral catalysts behave as efficient catalysts for obtaining asymmetric products without using chiral substrates.The best results were obtained when secondary benzyl amine 22 was treated with alkenyl boronate 21 and glyoxylate 23 to afford α-amino acid (R,E)-25 in 94% yield with 95:5 enantioselectivity (Scheme 6) [38].Moderate to good results were obtained when a number of substituted dibenzyl amines and boronates were employed.
Owing to the synthetic importance of amino acids (which are the building blocks of various peptides) [37], Lou and Schaus described the synthetic pathway for different amino acids (71-94%) using (S)-VAPOL catalyst 24 in 3Å MS/toluene mixture.These chiral catalysts behave as efficient catalysts for obtaining asymmetric products without using chiral substrates.The best results were obtained when secondary benzyl amine 22 was treated with alkenyl boronate 21 and glyoxylate 23 to afford α-amino acid (R,E)-25 in 94% yield with 95:5 enantioselectivity (Scheme 6) [38].Moderate to good results were obtained when a number of substituted dibenzyl amines and boronates were employed.Scheme 6. Synthetic pathway for amino acid 25.

Acid-Catalyzed Petasis Reaction
Reddy et al. described the lanthanum-catalyzed Petasis reaction under microwave irradiation by giving an 80-98% yield range of the desired products.The highest yield (98%) of tertiary amine 27 was recorded when aldehyde 5 was treated with morpholine 14 and (2-chlorophenyl)boronic acid 26 under microwave irradiation using La(OTf) 3 catalyst (Scheme 7).However, by using benzaldehydes (instead of salicylaldehydes) under the same reaction conditions, moderate yields of the corresponding products were observed (two examples, 75% and 78% yields) [39].

Acid-Catalyzed Petasis Reaction
Reddy et al. described the lanthanum-catalyzed Petasis reaction under microwave irradiation by giving an 80-98% yield range of the desired products.The highest yield (98%) of tertiary amine 27 was recorded when aldehyde 5 was treated with morpholine 14 and (2-chlorophenyl)boronic acid 26 under microwave irradiation using La(OTf)3 catalyst (Scheme 7).However, by using benzaldehydes (instead of salicylaldehydes) under the same reaction conditions, moderate yields of the corresponding products were observed (two examples, 75% and 78% yields) [39].Vinylglycines or β,γ-unsaturated α-amino acids represent a unique class of optically pure nonproteinogenic amino acids, which display antimicrobial activity and act as synthetic intermediates in various organic transformations [40].The synthesis of the aforementioned amino acids has been a tedious task.In this respect, Li and Xu in 2012 demonstrated an InBr3-catalyzed Petasis reaction to afford the desired amino acids within a short time in moderate to good yields (57-78%) yield range with high selectivities (up to 99%).The approach employed for that purpose includes Lewis acid as a practical and mild strategy to access functionally diverse products possessing high enantioselectivities.For example, α-(2-benzofuranyl)-glycine 31 was obtained in maximum yield (78%) with 99% diastereoselectivity through the reaction of benzofuran-2-boronic acid 28 with N-t-butanesulfinamide 29 and glyoxylic acid 30 using InBr3 in dichloromethane at r.t.(Scheme 8) [41].A variety of styryl substituted boronic acids with 4-Me, 4-OMe, 4-F, 4-Cl, 3-Cl, 4-CF3, 4-Ph and benzothiophene substitutions gave moderate yields when reacted.The target compounds obtained by this methodology have found a variety of applications in asymmetric and medicinal synthesis.Vinylglycines or β,γ-unsaturated α-amino acids represent a unique class of optically pure nonproteinogenic amino acids, which display antimicrobial activity and act as synthetic intermediates in various organic transformations [40].The synthesis of the aforementioned amino acids has been a tedious task.In this respect, Li and Xu in 2012 demonstrated an InBr 3 -catalyzed Petasis reaction to afford the desired amino acids within a short time in moderate to good yields (57-78%) yield range with high selectivities (up to 99%).The approach employed for that purpose includes Lewis acid as a practical and mild strategy to access functionally diverse products possessing high enantioselectivities.For example, α-(2-benzofuranyl)-glycine 31 was obtained in maximum yield (78%) with 99% diastereoselectivity through the reaction of benzofuran-2-boronic acid 28 with N-t-butanesulfinamide 29 and glyoxylic acid 30 using InBr 3 in dichloromethane at r.t.(Scheme 8) [41].A variety of styryl substituted boronic acids with 4-Me, 4-OMe, 4-F, 4-Cl, 3-Cl, 4-CF 3 , 4-Ph and benzothiophene substitutions gave moderate yields when reacted.The target compounds obtained by this methodology have found a variety of applications in asymmetric and medicinal synthesis.

Acid-Catalyzed Petasis Reaction
Reddy et al. described the lanthanum-catalyzed Petasis reaction under microwave irradiation by giving an 80-98% yield range of the desired products.The highest yield (98%) of tertiary amine 27 was recorded when aldehyde 5 was treated with morpholine 14 and (2-chlorophenyl)boronic acid 26 under microwave irradiation using La(OTf)3 catalyst (Scheme 7).However, by using benzaldehydes (instead of salicylaldehydes) under the same reaction conditions, moderate yields of the corresponding products were observed (two examples, 75% and 78% yields) [39].Vinylglycines or β,γ-unsaturated α-amino acids represent a unique class of optically pure nonproteinogenic amino acids, which display antimicrobial activity and act as synthetic intermediates in various organic transformations [40].The synthesis of the aforementioned amino acids has been a tedious task.In this respect, Li and Xu in 2012 demonstrated an InBr3-catalyzed Petasis reaction to afford the desired amino acids within a short time in moderate to good yields (57-78%) yield range with high selectivities (up to 99%).The approach employed for that purpose includes Lewis acid as a practical and mild strategy to access functionally diverse products possessing high enantioselectivities.For example, α-(2-benzofuranyl)-glycine 31 was obtained in maximum yield (78%) with 99% diastereoselectivity through the reaction of benzofuran-2-boronic acid 28 with N-t-butanesulfinamide 29 and glyoxylic acid 30 using InBr3 in dichloromethane at r.t.(Scheme 8) [41].A variety of styryl substituted boronic acids with 4-Me, 4-OMe, 4-F, 4-Cl, 3-Cl, 4-CF3, 4-Ph and benzothiophene substitutions gave moderate yields when reacted.The target compounds obtained by this methodology have found a variety of applications in asymmetric and medicinal synthesis.Zhang et al. developed a direct approach for the preparation of azaarene-based glycines (65-94% yield range) through a trifluoroacetic acid (TFA)-promoted Petasis reaction.Trifluoroacetic acid acted as an efficient medium for carrying out the synthesis of arylglycine derived from indoline in the presence of dichloromethane at room temperature.
olecules 2023, 28, x FOR PEER REVIEW 9 of 21 arylglycine derived from indoline in the presence of dichloromethane at room temperature.A highlighted pathway is presented in Scheme 9, according to which the reaction of glyoxylic acid 30 with 5-nitroindoline 32 and boronic acid 33 gave indoline-derived glycine 34 in 94% yield using TFA in DCM solvent (Scheme 9) [42].The effect of various boronic acids bearing 4-methyl, 4-ethyl, 4-isopropyl, 3,5-dimethyl, 4-methoxy, 3,4,5-trimethoxy, 3,4-(1,4-dioxan-2,3-diyl), 4-SCH3, 4-chloro, 4-bromo, 3,5-dibromo, 4-CO2CH3, 4-CF3, 3,5-di-CF3, 4-CH2Br, 4-CH2Ph and 4-NO2 was also demonstrated.The extensive utilization of organotrifluoroborate salts in palladium-and rhodium-catalyzed reactions increases the importance of these salts in organic chemistry [43].In this regard, these borate salts were added to imine and enamine by Carrera in 2017 using a stoichiometric amount of TFA for the preparation of diversified amines (65-99%).For that purpose, a boronate complex with a catalytic amount of trifluoroacetic acid was synthesized and employed as nucleophiles.The complexes exhibit moisture and air stability and are easily available.A highlighted example is presented in Scheme 10 [44].A Petasis reaction of imine 35 with trifluoroborate 36 in the presence of acetonitrile at 23 °C afforded corresponding product 37 in 99% yield.Additionally, thiophene substituted imine 35; the effect of 4-OMePh, 4-CF3Ph, 3-MePh, furan-yl, n-propyl, benzyl, heptenyl and isopropyl substitutions on the imine component were also observed.Allylic alcohol has been broadly used to construct different types of natural products, for instance, alotaketal A and lehualides [45,46].In this respect, Ding et al. performed a hydrochloric acid (HCl) promoted Petasis methodology for the preparation of allylic alcohols (36-98%).The use of HCl provided a smooth and efficient protocol to obtain a variety of amines having a heteroaromatic ring at adjacent positions.A highlighted example is described in Scheme 11 [47].2-Pyridinecarbaldehyde 38, cyclic amine 40 and oxaborole 39 were subjected to a Petasis reaction using HCl in acetonitrile at 80 °C to afford the expected allylic alcohol 41 in 98% yield.It was observed that electron-donating groups such as alkyl and aryl on an oxaborole moiety gave a good to excellent yield (75-92%), while the methoxyl group resulted in a lesser yield (60%), but the overall yield range of these groups is good in contrast to electron-withdrawing substituents.Similarly, the effect of cyclic and acyclic amines was investigated.It was observed that cyclic amines gave the Petasis products in an excellent yield (82-96%) compared to acyclic amines (48-56%).The extensive utilization of organotrifluoroborate salts in palladium-and rhodiumcatalyzed reactions increases the importance of these salts in organic chemistry [43].In this regard, these borate salts were added to imine and enamine by Carrera in 2017 using a stoichiometric amount of TFA for the preparation of diversified amines (65-99%).For that purpose, a boronate complex with a catalytic amount of trifluoroacetic acid was synthesized and employed as nucleophiles.The complexes exhibit moisture and air stability and are easily available.A highlighted example is presented in Scheme 10 [44].A Petasis reaction of imine 35 with trifluoroborate 36 in the presence of acetonitrile at 23 • C afforded corresponding product 37 in 99% yield.Additionally, thiophene substituted imine 35; the effect of 4-OMePh, 4-CF 3 Ph, 3-MePh, furan-yl, n-propyl, benzyl, heptenyl and isopropyl substitutions on the imine component were also observed.
les 2023, 28, x FOR PEER REVIEW 9 of 21 arylglycine derived from indoline in the presence of dichloromethane at room temperature.A highlighted pathway is presented in Scheme 9, according to which the reaction of glyoxylic acid 30 with 5-nitroindoline 32 and boronic acid 33 gave indoline-derived glycine 34 in 94% yield using TFA in DCM solvent (Scheme 9) [42].The effect of various boronic acids bearing 4-methyl, 4-ethyl, 4-isopropyl, 3,5-dimethyl, 4-methoxy, 3,4,5-trimethoxy, 3,4-(1,4-dioxan-2,3-diyl), 4-SCH3, 4-chloro, 4-bromo, 3,5-dibromo, 4-CO2CH3, 4-CF3, 3,5-di-CF3, 4-CH2Br, 4-CH2Ph and 4-NO2 was also demonstrated.The extensive utilization of organotrifluoroborate salts in palladium-and rhodium-catalyzed reactions increases the importance of these salts in organic chemistry [43].In this regard, these borate salts were added to imine and enamine by Carrera in 2017 using a stoichiometric amount of TFA for the preparation of diversified amines (65-99%).For that purpose, a boronate complex with a catalytic amount of trifluoroacetic acid was synthesized and employed as nucleophiles.The complexes exhibit moisture and air stability and are easily available.A highlighted example is presented in Scheme 10 [44].A Petasis reaction of imine 35 with trifluoroborate 36 in the presence of acetonitrile at 23 °C afforded corresponding product 37 in 99% yield.Additionally, thiophene substituted imine 35; the effect of 4-OMePh, 4-CF3Ph, 3-MePh, furan-yl, n-propyl, benzyl, heptenyl and isopropyl substitutions on the imine component were also observed.Allylic alcohol has been broadly used to construct different types of natural products, for instance, alotaketal A and lehualides [45,46].In this respect, Ding et al. performed a hydrochloric acid (HCl) promoted Petasis methodology for the preparation of allylic alcohols (36-98%).The use of HCl provided a smooth and efficient protocol to obtain a variety of amines having a heteroaromatic ring at adjacent positions.A highlighted example is described in Scheme 11 [47].2-Pyridinecarbaldehyde 38, cyclic amine 40 and oxaborole 39 were subjected to a Petasis reaction using HCl in acetonitrile at 80 °C to afford the expected allylic alcohol 41 in 98% yield.It was observed that electron-donating groups such as alkyl and aryl on an oxaborole moiety gave a good to excellent yield (75-92%), while the methoxyl group resulted in a lesser yield (60%), but the overall yield range of these groups is good in contrast to electron-withdrawing substituents.Similarly, the effect of cyclic and acyclic amines was investigated.It was observed that cyclic amines gave the Petasis products in an excellent yield (82-96%) compared to acyclic amines (48-56%).Allylic alcohol has been broadly used to construct different types of natural products, for instance, alotaketal A and lehualides [45,46].In this respect, Ding et al. performed a hydrochloric acid (HCl) promoted Petasis methodology for the preparation of allylic alcohols (36-98%).The use of HCl provided a smooth and efficient protocol to obtain a variety of amines having a heteroaromatic ring at adjacent positions.A highlighted example is described in Scheme 11 [47].2-Pyridinecarbaldehyde 38, cyclic amine 40 and oxaborole 39 were subjected to a Petasis reaction using HCl in acetonitrile at 80 • C to afford the expected allylic alcohol 41 in 98% yield.It was observed that electron-donating groups such as alkyl and aryl on an oxaborole moiety gave a good to excellent yield (75-92%), while the methoxyl group resulted in a lesser yield (60%), but the overall yield range of these groups is good in contrast to electron-withdrawing substituents.Similarly, the effect of cyclic and acyclic amines was investigated.It was observed that cyclic amines gave the Petasis products in an excellent yield (82-96%) compared to acyclic amines (48-56%).Scheme 11.Synthesis of allylic alcohol 41.

Catalyst-Free Petasis Reaction
The use of transition metal-catalyzed multicomponent reactions has been a way to go for synthesizing natural products and derivatives.But these approaches pose serious hazards to the environment, causing pollution and posing difficulties in separation.These problems have been tackled by devising a catalyst-free synthesis.Considering the synthetic utility of propargylamines in natural product synthesis [48], the preparation of N-benzyl propargylamines (31-94%) was attained under a catalyst-free environment by Feng et al.Maximum yield (94%) was obtained when benzylamine 42 was reacted with propiolic acid 43, boronic acid 15 and formaldehyde 44 in 1,2-dichloroethane at 45 °C (Scheme 12) [49].The benzyl amine component with 4-Cl, 2-Cl, 4-F, 4-Br, 4-CN, 2-Me, 3-Me, 4-Me, 2-OMe, 4-OMe and 3,4-OMe, along with cyclohexyl and methoxy propyl substitutions, were employed.A variety of boronic acids with different substitutions (Ph, 3-ClPh, 3-FPh, biphenyl, 3-OMePh, naphthyl, 3-thiophene, 4-FPh, 4-MePh, 2-OMePh and 4-OMePh) and propiolic acids bearing (2-FPh, 4-CF3Ph, 4-OMePh, biphenyl, 4-tBuPh, butyl, propyl and methyl) substitutions were also employed to demonstrate the substrate scope of developed procedure.This methodology accommodated a number of advantages over metal-catalyzed reactions, providing a wide substrate scope, mild reaction conditions and chemoselective products.Antimicrobial, antiallergic, antitubercular and herbicidal properties of oxazolidines make them suitable candidates in medicinal chemistry.This significant moiety not only act as chiral auxiliaries in asymmetric synthesis but also as ligands for catalysts based on transition metal [50].In this respect, Zheng et al. presented synthetic pathway for oxazolidines (43-85%) by the reaction of a variety of organoboronic acids with 1,2-amino alcohols and formaldehyde.For that purpose, a catalyst-free, facile and effective methodology was adopted.The maximum yield of respective product 48 (85%) was attained by the treatment of phenyl boronic acid 47 with 1,2-amino alcohol 46 and formaldehyde 44 in toluene at 80 °C (Scheme 13) [51].The usage of a number of substituted aminoeth-Scheme 11.Synthesis of allylic alcohol 41.

Catalyst-Free Petasis Reaction
The use of transition metal-catalyzed multicomponent reactions has been a way to go for synthesizing natural products and derivatives.But these approaches pose serious hazards to the environment, causing pollution and posing difficulties in separation.These problems have been tackled by devising a catalyst-free synthesis.Considering the synthetic utility of propargylamines in natural product synthesis [48], the preparation of N-benzyl propargylamines (31-94%) was attained under a catalyst-free environment by Feng et al.Maximum yield (94%) was obtained when benzylamine 42 was reacted with propiolic acid 43, boronic acid 15 and formaldehyde 44 in 1,2-dichloroethane at 45 °C (Scheme 12) [49].The benzyl amine component with 4-Cl, 2-Cl, 4-F, 4-Br, 4-CN, 2-Me, 3-Me, 4-Me, 2-OMe, 4-OMe and 3,4-OMe, along with cyclohexyl and methoxy propyl substitutions, were employed.A variety of boronic acids with different substitutions (Ph, 3-ClPh, 3-FPh, biphenyl, 3-OMePh, naphthyl, 3-thiophene, 4-FPh, 4-MePh, 2-OMePh and 4-OMePh) and propiolic acids bearing (2-FPh, 4-CF3Ph, 4-OMePh, biphenyl, 4-tBuPh, butyl, propyl and methyl) substitutions were also employed to demonstrate the substrate scope of developed procedure.This methodology accommodated a number of advantages over metal-catalyzed reactions, providing a wide substrate scope, mild reaction conditions and chemoselective products.Antimicrobial, antiallergic, antitubercular and herbicidal properties of oxazolidines make them suitable candidates in medicinal chemistry.This significant moiety not only act as chiral auxiliaries in asymmetric synthesis but also as ligands for catalysts based on transition metal [50].In this respect, Zheng et al. presented synthetic pathway for oxazolidines (43-85%) by the reaction of a variety of organoboronic acids with 1,2-amino alcohols and formaldehyde.For that purpose, a catalyst-free, facile and effective methodology was adopted.The maximum yield of respective product 48 (85%) was attained by the treatment of phenyl boronic acid 47 with 1,2-amino alcohol 46 and formaldehyde 44 in toluene at 80 °C (Scheme 13) [51].The usage of a number of substituted aminoeth- Antimicrobial, antiallergic, antitubercular and herbicidal properties of oxazolidines make them suitable candidates in medicinal chemistry.This significant moiety not only act as chiral auxiliaries in asymmetric synthesis but also as ligands for catalysts based on transition metal [50].In this respect, Zheng et al. presented synthetic pathway for oxazolidines (43-85%) by the reaction of a variety of organoboronic acids with 1,2-amino alcohols and formaldehyde.For that purpose, a catalyst-free, facile and effective methodology was adopted.The maximum yield of respective product 48 (85%) was attained by the treatment of phenyl boronic acid 47 with 1,2-amino alcohol 46 and formaldehyde 44 in toluene at 80 • C (Scheme 13) [51].The usage of a number of substituted aminoethanols bearing Me and Ph as well as styryl and phenyl boronic acids having (4-OMe, 2-OMe, 4-Me, 4-Cl, 2-Me, 3-OMe, 2-F, 4-F, 4-CF 3 , 4-tBu) substitutions elucidate the wide substrate scope.Chiral α-aryl glycines have served as valuable scaffolds due to a variety of applications in the fields of pharmaceutical, biological and synthetic chemistry [52].Considering their importance, Nanda and Trotter elaborated a Petasis-boronic acid-Mannich reaction using HFIP (hexafluoroisopropanol) as an additive in DCM (CH2Cl2) at r.t.After applying these conditions on different pyrrolidines (2-Me, 2-isopropyl, 2-phenyl, 2-methoxymethyl, 2,5-dimethyl, 3-NHBoc) and 2-methylpiperidine, glyoxylic acid monohydrates and different types of aryl boronic acids (Ph, 2-MePh, 4-OMePh, 4-FPh, 3-FPh, 3-F-4-OBnPh, 3-CNPh, thiophen-2-yl and thiophene-3-yl) furnished moderate to high yields (59-96%) of the targeted compounds.To achieve best results (96% yield), amine rac-49 was treated with phenylboronic acid 9 and glyoxylic acid monohydrate 30 to obtain compound 50 with a 95:5 diastereomeric ratio (Scheme 14) [53].The main attributes of this reaction included the employment of HFIP as a co-solvent, which significantly enhanced the reaction quality by reducing the duration of the reaction.The synthesis of natural products has been carried out via a number of strategies [54].Natural products having quinoline rings display excellent antibacterial, antidiabetic and anti-inflammatory activities [55].Nitrogen-containing compounds are considered significant among various natural compounds, i.e., alkaloids.In this respect, Chang et al. proposed a novel synthetic pathway for dihydroquinolines and dihydroisoquinolines.The synthesis of substituted dihydro isoquinoline was carried out by treating 2-benzofuranboronic acid with several isoquinolines.For example, the treatment of isoquinoline 51 with 2-benzofuranboronic acid 28 using DEPC (diethyl pyrocarbonate) and DCM as a solvent at r.t.gave dihydroisoquinoline 52 in 97.5% yield (Scheme 15) [56].By employing substituted quinolines with substitutions (6-yl pivalate, 3-methyl, 6-methyl, 6-yl-pivalamide and 6-nitro), substrate scalability of this method was proved and furnished high yields of respective target compounds.The main features of this methodology include simple experiments, good yields and facile reaction conditions.Scheme 13.Synthetic method for N-substituted 1,3-oxazolidine 48.
Chiral α-aryl glycines have served as valuable scaffolds due to a variety of applications in the fields of pharmaceutical, biological and synthetic chemistry [52].Considering their importance, Nanda and Trotter elaborated a Petasis-boronic acid-Mannich reaction using HFIP (hexafluoroisopropanol) as an additive in DCM (CH 2 Cl 2 ) at r.t.After applying these conditions on different pyrrolidines (2-Me, 2-isopropyl, 2-phenyl, 2-methoxymethyl, 2,5dimethyl, 3-NHBoc) and 2-methylpiperidine, glyoxylic acid monohydrates and different types of aryl boronic acids (Ph, 2-MePh, 4-OMePh, 4-FPh, 3-FPh, 3-F-4-OBnPh, 3-CNPh, thiophen-2-yl and thiophene-3-yl) furnished moderate to high yields (59-96%) of the targeted compounds.To achieve best results (96% yield), amine rac-49 was treated with phenylboronic acid 9 and glyoxylic acid monohydrate 30 to obtain compound 50 with a 95:5 diastereomeric ratio (Scheme 14) [53].The main attributes of this reaction included the employment of HFIP as a co-solvent, which significantly enhanced the reaction quality by reducing the duration of the reaction.Chiral α-aryl glycines have served as valuable scaffolds due to a variety of applications in the fields of pharmaceutical, biological and synthetic chemistry [52].Considering their importance, Nanda and Trotter elaborated a Petasis-boronic acid-Mannich reaction using HFIP (hexafluoroisopropanol) as an additive in DCM (CH2Cl2) at r.t.After applying these conditions on different pyrrolidines (2-Me, 2-isopropyl, 2-phenyl, 2-methoxymethyl, 2,5-dimethyl, 3-NHBoc) and 2-methylpiperidine, glyoxylic acid monohydrates and different types of aryl boronic acids (Ph, 2-MePh, 4-OMePh, 4-FPh, 3-FPh, 3-F-4-OBnPh, 3-CNPh, thiophen-2-yl and thiophene-3-yl) furnished moderate to high yields (59-96%) of the targeted compounds.To achieve best results (96% yield), amine rac-49 was treated with phenylboronic acid 9 and glyoxylic acid monohydrate 30 to obtain compound 50 with a 95:5 diastereomeric ratio (Scheme 14) [53].The main attributes of this reaction included the employment of HFIP as a co-solvent, which significantly enhanced the reaction quality by reducing the duration of the reaction.The synthesis of natural products has been carried out via a number of strategies [54].Natural products having quinoline rings display excellent antibacterial, antidiabetic and anti-inflammatory activities [55].Nitrogen-containing compounds are considered significant among various natural compounds, i.e., alkaloids.In this respect, Chang et al. proposed a novel synthetic pathway for dihydroquinolines and dihydroisoquinolines.The synthesis of substituted dihydro isoquinoline was carried out by treating 2-benzofuranboronic acid with several isoquinolines.For example, the treatment of isoquinoline 51 with 2-benzofuranboronic acid 28 using DEPC (diethyl pyrocarbonate) and DCM as a solvent at r.t.gave dihydroisoquinoline 52 in 97.5% yield (Scheme 15) [56].By employing substituted quinolines with substitutions (6-yl pivalate, 3-methyl, 6-methyl, 6-yl-pivalamide and 6-nitro), substrate scalability of this method was proved and furnished high yields of respective target compounds.The main features of this methodology include simple experiments, good yields and facile reaction conditions.The synthesis of natural products has been carried out via a number of strategies [54].Natural products having quinoline rings display excellent antibacterial, antidiabetic and anti-inflammatory activities [55].Nitrogen-containing compounds are considered significant among various natural compounds, i.e., alkaloids.In this respect, Chang et al. proposed a novel synthetic pathway for dihydroquinolines and dihydroisoquinolines.The synthesis of substituted dihydro isoquinoline was carried out by treating 2-benzofuranboronic acid with several isoquinolines.For example, the treatment of isoquinoline 51 with 2benzofuranboronic acid 28 using DEPC (diethyl pyrocarbonate) and DCM as a solvent at r.t.gave dihydroisoquinoline 52 in 97.5% yield (Scheme 15) [56].By employing substituted quinolines with substitutions (6-yl pivalate, 3-methyl, 6-methyl, 6-yl-pivalamide and 6-nitro), substrate scalability of this method was proved and furnished high yields of respective target compounds.The main features of this methodology include simple experiments, good yields and facile reaction conditions.Ionic liquids are efficient and unusual solvent systems introduced in recent years.These consist of almost five anions and cations.The selection of ionic liquids for some reaction depends upon the nature of reagents, the attributes of ionic liquids and the reaction conditions.These can be efficiently utilized as solvents for reaction chemistry, including catalytic reactions, due to their most attractive property, i.e., a lack of volatility [57].Alkylaminophenols (70-85%) were prepared by Yadav via an ionic liquid-accelerated Petasis reaction involving salicylaldehydes bearing 6-methoxy and 6-ethoxy, amines (morpholine, 4-methylpiperidine, pyrrolidine, N-methyl-1-phenylmethanamine and t-butyl piperidin-3-ylcarbamate) and boronic acids (1,1-biphenyl, naphthalene, thiophene and benzodioxol-5-yl).The excellent yield of alkylaminophenol 56 (85%) was obtained via the Petasis reaction of an aldehyde 53 with cyclic amine 54 and aryl boronic acid 55 at r.t. in [Bmim]BF4 (Scheme 16) [58].The increased reactivity of boronic acids due to the ionic liquid led to the better yields and reduced reaction durations.The facile separation of the catalyst from the reaction mixture and its reuse makes it a good candidate as a green catalyst.The prevalence of different forms of cancers and discovery of different compounds for their treatment have been a persistent part of research [59].Dihydropyrone (DHP)-based natural products show antioxidant, spasmolytic, anticancer, antibacterial, antianaphylactic and anti-HIV activity [60].A protocol for the preparation of functionalized dihydropyrones using DCM and i-PrOH as a reaction medium was developed by Li et al.In their methodology, 3,6-dihydropyrones were obtained in 78-98% yield, and a 45-98% yield range was observed in the case of 5,6-dihydropyrones.Amine 58 and glyoxylic acid 30 were reacted with oxaboroles 57 in DCM at 40 °C and in i-PrOH at 80 °C to afford 3,6-DHP 59 (98%) and 5,6-DHP 60 (98%), respectively (Scheme 17) [61].The synthesis of target compounds in high regioselectivities accounts as the prominent attributes of this methodology.Ionic liquids are efficient and unusual solvent systems introduced in recent years.These consist of almost five anions and cations.The selection of ionic liquids for some reaction depends upon the nature of reagents, the attributes of ionic liquids and the reaction conditions.These can be efficiently utilized as solvents for reaction chemistry, including catalytic reactions, due to their most attractive property, i.e., a lack of volatility [57].Alkylaminophenols (70-85%) were prepared by Yadav via an ionic liquid-accelerated Petasis reaction involving salicylaldehydes bearing 6-methoxy and 6-ethoxy, amines (morpholine, 4-methylpiperidine, pyrrolidine, N-methyl-1-phenylmethanamine and t-butyl piperidin-3-ylcarbamate) and boronic acids (1,1-biphenyl, naphthalene, thiophene and benzodioxol-5-yl).The excellent yield of alkylaminophenol 56 (85%) was obtained via the Petasis reaction of an aldehyde 53 with cyclic amine 54 and aryl boronic acid 55 at r.t. in [Bmim]BF 4 (Scheme 16) [58].The increased reactivity of boronic acids due to the ionic liquid led to the better yields and reduced reaction durations.The facile separation of the catalyst from the reaction mixture and its reuse makes it a good candidate as a green catalyst.Ionic liquids are efficient and unusual solvent systems introduced in recent years.These consist of almost five anions and cations.The selection of ionic liquids for some reaction depends upon the nature of reagents, the attributes of ionic liquids and the reaction conditions.These can be efficiently utilized as solvents for reaction chemistry, including catalytic reactions, due to their most attractive property, i.e., a lack of volatility [57].Alkylaminophenols (70-85%) were prepared by Yadav via an ionic liquid-accelerated Petasis reaction involving salicylaldehydes bearing 6-methoxy and 6-ethoxy, amines (morpholine, 4-methylpiperidine, pyrrolidine, N-methyl-1-phenylmethanamine and t-butyl piperidin-3-ylcarbamate) and boronic acids (1,1-biphenyl, naphthalene, thiophene and benzodioxol-5-yl).The excellent yield of alkylaminophenol 56 (85%) was obtained via the Petasis reaction of an aldehyde 53 with cyclic amine 54 and aryl boronic acid 55 at r.t. in [Bmim]BF4 (Scheme 16) [58].The increased reactivity of boronic acids due to the ionic liquid led to the better yields and reduced reaction durations.The facile separation of the catalyst from the reaction mixture and its reuse makes it a good candidate as a green catalyst.The prevalence of different forms of cancers and discovery of different compounds for their treatment have been a persistent part of research [59].Dihydropyrone (DHP)-based natural products show antioxidant, spasmolytic, anticancer, antibacterial, antianaphylactic and anti-HIV activity [60].A protocol for the preparation of functionalized dihydropyrones using DCM and i-PrOH as a reaction medium was developed by Li et al.In their methodology, 3,6-dihydropyrones were obtained in 78-98% yield, and a 45-98% yield range was observed in the case of 5,6-dihydropyrones.Amine 58 and glyoxylic acid 30 were reacted with oxaboroles 57 in DCM at 40 °C and in i-PrOH at 80 °C to afford 3,6-DHP 59 (98%) and 5,6-DHP 60 (98%), respectively (Scheme 17) [61].The synthesis of target compounds in high regioselectivities accounts as the prominent attributes of this methodology.The prevalence of different forms of cancers and discovery of different compounds for their treatment have been a persistent part of research [59].Dihydropyrone (DHP)-based natural products show antioxidant, spasmolytic, anticancer, antibacterial, antianaphylactic and anti-HIV activity [60].A protocol for the preparation of functionalized dihydropyrones using DCM and i-PrOH as a reaction medium was developed by Li et al.In their methodology, 3,6-dihydropyrones were obtained in 78-98% yield, and a 45-98% yield range was observed in the case of 5,6-dihydropyrones.Amine 58 and glyoxylic acid 30 were reacted with oxaboroles 57 in DCM at 40 • C and in i-PrOH at 80 • C to afford 3,6-DHP 59 (98%) and 5,6-DHP 60 (98%), respectively (Scheme 17) [61].The synthesis of target compounds in high regioselectivities accounts as the prominent attributes of this methodology.Deep eutectic solvents are unusual liquids with a bunch of useful properties, such as high chemical and thermal stability, dissolution capacity and vapor pressure.Additionally, they are environment friendly alternatives to conventional solvents owing to their reusability.Azizi et al. proposed a deep eutectic solvent-based synthesis of alkylaminophenol derivatives in good to moderate yields.The target compounds were obtained through a reaction of salicylaldehyde 5, morpholine 14 and phenylboronic acid 9 (Scheme 18) [62].The aminomethyl phenol scaffold exhibits a variety of applications in agrochemicals, pharmaceuticals and plant protection.To achieve the synthesis of this moiety, Di et al. reported a catalyst-free Petasis-borono-Mannich reaction to give a variety of substituted aminomethyl phenol derivatives.The reaction was carried out in the presence of cyclopentyl methyl ether at 80 °C between substituted salicylaldehydes, secondary amines and a variety of boronic acids to furnish final compounds in low to moderate yields.The best yield was obtained when 5-bromo salicylaldehyde 62, fused boronic acid 64 and amine 63 were made to react in the presence of cyclopentyl methyl ether (CPME) at 80 °C.The characteristic features of this reaction are green and toxic-free reaction conditions, ease of operation and the use of CPME as a solvent furnishing target compounds in good yields (Scheme 19) [63].Deep eutectic solvents are unusual liquids with a bunch of useful properties, such as high chemical and thermal stability, dissolution capacity and vapor pressure.Additionally, they are environment friendly alternatives to conventional solvents owing to their reusability.Azizi et al. proposed a deep eutectic solvent-based synthesis of alkylaminophenol derivatives in good to moderate yields.The target compounds were obtained through a reaction of salicylaldehyde 5, morpholine 14 and phenylboronic acid 9 (Scheme 18) [62].Deep eutectic solvents are unusual liquids with a bunch of useful properties, such as high chemical and thermal stability, dissolution capacity and vapor pressure.Additionally, they are environment friendly alternatives to conventional solvents owing to their reusability.Azizi et al. proposed a deep eutectic solvent-based synthesis of alkylaminophenol derivatives in good to moderate yields.The target compounds were obtained through a reaction of salicylaldehyde 5, morpholine 14 and phenylboronic acid 9 (Scheme 18) [62].The aminomethyl phenol scaffold exhibits a variety of applications in agrochemicals, pharmaceuticals and plant protection.To achieve the synthesis of this moiety, Di et al. reported a catalyst-free Petasis-borono-Mannich reaction to give a variety of substituted aminomethyl phenol derivatives.The reaction was carried out in the presence of cyclopentyl methyl ether at 80 °C between substituted salicylaldehydes, secondary amines and a variety of boronic acids to furnish final compounds in low to moderate yields.The best yield was obtained when 5-bromo salicylaldehyde 62, fused boronic acid 64 and amine 63 were made to react in the presence of cyclopentyl methyl ether (CPME) at 80 °C.The characteristic features of this reaction are green and toxic-free reaction conditions, ease of operation and the use of CPME as a solvent furnishing target compounds in good yields (Scheme 19) [63].The aminomethyl phenol scaffold exhibits a variety of applications in agrochemicals, pharmaceuticals and plant protection.To achieve the synthesis of this moiety, Di et al. reported a catalyst-free Petasis-borono-Mannich reaction to give a variety of substituted aminomethyl phenol derivatives.The reaction was carried out in the presence of cyclopentyl methyl ether at 80 • C between substituted salicylaldehydes, secondary amines and a variety of boronic acids to furnish final compounds in low to moderate yields.The best yield was obtained when 5-bromo salicylaldehyde 62, fused boronic acid 64 and amine 63 were made to react in the presence of cyclopentyl methyl ether (CPME) at 80 • C. The characteristic features of this reaction are green and toxic-free reaction conditions, ease of operation and the use of CPME as a solvent furnishing target compounds in good yields (Scheme 19) [63].

Base-Catalyzed Petasis Reaction
Various synthetic strategies for 2,5-dihydrofuran have been reported because of

Base-Catalyzed Petasis Reaction
Various synthetic strategies for 2,5-dihydrofuran have been reported because of their extensive involvement in the synthesis of natural products [72].Cui et al. presented the amine-promoted formation of 2,5-dihydrofurans in 71-92% yield.To achieve the desired compounds, a number of amines were tried and tested to obtain the best condition, among which secondary amines bearing electron-rich alkyl groups exhibited higher yields.An exemplary substrate is presented in Scheme 23 [73].2,5-Dihydrofuran 74 was obtained in 92% yield by the Petasis reaction of salicylaldehyde 5, morpholine 14 and oxaborole 39 at 85 °C.A variety of substituted salicylaldehydes having 5-I, 3,5-t-butyl, Scheme 22. Synthetic pathway for quinoxaline 73.

Base-Catalyzed Petasis Reaction
Various synthetic strategies for 2,5-dihydrofuran have been reported because of their involvement in the synthesis of natural products [72].Cui et al. presented the amine-promoted formation of 2,5-dihydrofurans in 71-92% yield.To achieve the desired compounds, a number of amines were tried and tested to obtain the best condition, among which secondary amines bearing electron-rich alkyl groups exhibited higher yields.An exemplary substrate is presented in Scheme 23 [73].2,5-Dihydrofuran 74 was obtained in 92% yield by the Petasis reaction of salicylaldehyde 5, morpholine 14 and oxaborole 39 at 85 • C. A variety of substituted salicylaldehydes having 5-I, 3,5-t-butyl, 5-NO 2 , 5-Br, 3-Me and 3-OMe substitutions and oxaborole with phenyl, ethylbenzene, p-tolyl, m-tolyl, ethyl and butyl substitutions were also employed for this methodology.
FOR PEER REVIEW 16 of 21 5-NO2, 5-Br, 3-Me and 3-OMe substitutions and oxaborole with phenyl, ethylbenzene, p-tolyl, m-tolyl, ethyl and butyl substitutions were also employed for this methodology.The combination of amino acids and different polymers gives unique characteristics to the resulting compounds [74].Takahashi and Kakuchi optimized reaction conditions to attain polymers through the coupling of aromatic boronic acids, amines and glyoxylic acids by using AIBN (2,2′-Azobis(isobutyronitrile)) in 2021.The use of derivatives of boronic acid causes some disadvantages.This problem was tackled by using MIDA esters of boronic acid, which were further polymerized to yield poly amino acids.For this purpose, boronic acid was protected with N-methyliminodiacetic acid (MIDA) ester.MIDA ester substituted with styrene 75 underwent free-radical polymerization in an AIBN/DMSO mixture and converted into polymer (PSt-BMIDA) 76 with 98.4% yield.Furthermore, synthesized polymer (PSt-BMIDA) 76 was subjected to a Petasis reaction with dibenzylamine 77 and glyoxylic acid 30 using a tetramethyl ammonium hydroxide (TMAOH) base in DMSO to afford the poly (α-amino acid) 78 (73.1%) (Scheme 24) [75].

Miscellaneous Catalysts
A natural polymer, chitosan, is used in hydrogels due to the polymer's biocompatibility, low toxicity and degradability [76].The research group of Reddy used chitosan in a Petasis-borono-Mannich reaction for the construction of alkylaminophenols.Besides giving an excellent yield range, this catalyst can be recycled up to ten times, which highlights the significance of this method.The treatment of ortho-hydroxy aldehyde 5 with 4-chloro phenylboronic acid 79 and morpholine 14, under the optimized conditions (chitosan in 1,4-dioxane at 80 °C), afforded product 80 in 95% yield, as described in The combination of amino acids and different polymers gives unique characteristics to the resulting compounds [74].Takahashi and Kakuchi optimized reaction conditions to attain polymers through the coupling of aromatic boronic acids, amines and glyoxylic acids by using AIBN (2,2 -Azobis(isobutyronitrile)) in 2021.The use of derivatives of boronic acid causes some disadvantages.This problem was tackled by using MIDA esters of boronic acid, which were further polymerized to yield poly amino acids.For this purpose, boronic acid was protected with N-methyliminodiacetic acid (MIDA) ester.MIDA ester substituted with styrene 75 underwent free-radical polymerization in an AIBN/DMSO mixture and converted into polymer (PSt-BMIDA) 76 with 98.4% yield.Furthermore, synthesized polymer (PSt-BMIDA) 76 was subjected to a Petasis reaction with dibenzylamine 77 and glyoxylic acid 30 using a tetramethyl ammonium hydroxide (TMAOH) base in DMSO to afford the poly (α-amino acid) 78 (73.1%) (Scheme 24) [75].The combination of amino acids and different polymers gives unique characteristics to the resulting compounds [74].Takahashi and Kakuchi optimized reaction conditions to attain polymers through the coupling of aromatic boronic acids, amines and glyoxylic acids by using AIBN (2,2′-Azobis(isobutyronitrile)) in 2021.The use of derivatives of boronic acid causes some disadvantages.This problem was tackled by using MIDA esters of boronic acid, which were further polymerized to yield poly amino acids.For this purpose, boronic acid was protected with N-methyliminodiacetic acid (MIDA) ester.MIDA ester substituted with styrene 75 underwent free-radical polymerization in an AIBN/DMSO mixture and converted into polymer (PSt-BMIDA) 76 with 98.4% yield.Furthermore, synthesized polymer (PSt-BMIDA) 76 was subjected to a Petasis reaction with dibenzylamine 77 and glyoxylic acid 30 using a tetramethyl ammonium hydroxide (TMAOH) base in DMSO to afford the poly (α-amino acid) 78 (73.1%) (Scheme 24) [75].

Miscellaneous Catalysts
A natural polymer, chitosan, is used in hydrogels due to the polymer's biocompatibility, low toxicity and degradability [76].The research group of Reddy used chitosan in a Petasis-borono-Mannich reaction for the construction of alkylaminophenols.Besides giving an excellent yield range, this catalyst can be recycled up to ten times, which highlights the significance of this method.The treatment of ortho-hydroxy aldehyde 5 with 4-chloro phenylboronic acid 79 and morpholine 14, under the optimized conditions (chitosan in 1,4-dioxane at 80 • C), afforded product 80 in 95% yield, as described in Scheme 25 [77].Overall, a yield range of 86-95% was furnished when substituted 4-methoxy bearing salicylaldehyde was reacted with an amine component (morpholine, piperidine and pyrrolidine) and boronic acids with naphthyl and phenyl substitutions bearing 4-Cl, 4-OMe, 3,4-OMe, methoxycyclopropyl, 3-OMe, 2-Me, 4-Me, 3-NO 2 and 3,4,5-OMe.Photocatalysts are regarded as effective catalysts in radical-based reactions.Vytla et al. developed a photocatalyst ([Ir{dFCF3PPy}2(dtbpy)]PF6) and employed it for the synthesis of sulfonamides, amides and hydrazides via a Petasis reaction.The reaction took place between substituted aldehyde 81, substituted amines 82 and potassium cyclohexyltrifluoroborate 83 in the presence of photocatalyst, sodium bisulfate in dichloroethane for 24 h at room temperature.This three-component method is considered efficient as it has a wide substrate scope and requires mild reaction conditions (Scheme 26) [78].

Conclusions
On the basis of the literature reports discussed in this article, it is safe to conclude that the Petasis reaction is a highly efficient, atom-economical, one-pot, sustainable and waste-reducing approach.Synthetic methodologies based on the Petasis reaction have emerged as prestigious approaches to synthesize pharmaceutically relevant and structurally diverse scaffolds.This reaction proceeds well in the presence of different transition metal catalysts, Lewis acids, metal complexes bearing chiral ligands (BINOL), chitosan and ionic liquids.The functional group tolerance (substrate scope of this reaction) and diversity of the products obtained through this reaction are remarkable.groups have reported different alternate reaction protocols to achieve a Petasis reaction, and each methodology offers its own merits over the others, such as improved reaction yields, reduced reaction times, the recyclability of catalysts and mild reaction conditions.Albeit the extensive research conducted on Petasis reactions, the authors of this review article believe that there is still a great space to regarding the synthetic application of the Petasis reaction to produce natural products and drugs.Until now, only a few reports Photocatalysts are regarded as effective catalysts in radical-based reactions.Vytla et al. developed a photocatalyst ([Ir{dFCF 3 PPy} 2 (dtbpy)]PF 6 ) and employed it for the synthesis of sulfonamides, amides and hydrazides via a Petasis reaction.The reaction took place between substituted aldehyde 81, substituted amines 82 and potassium cyclohexyltrifluoroborate 83 in the presence of photocatalyst, sodium bisulfate in dichloroethane for 24 h at room temperature.This three-component method is considered efficient as it has a wide substrate scope and requires mild reaction conditions (Scheme 26) [78].Photocatalysts are regarded as effective catalysts in radical-based reactions.Vytla et al. developed a photocatalyst ([Ir{dFCF3PPy}2(dtbpy)]PF6) and employed it for the synthesis of sulfonamides, amides and hydrazides via a Petasis reaction.The reaction took place between substituted aldehyde 81, substituted amines 82 and potassium cyclohexyltrifluoroborate 83 in the presence of photocatalyst, sodium bisulfate in dichloroethane for 24 h at room temperature.This three-component method is considered efficient as it has a wide substrate scope and requires mild reaction conditions (Scheme 26) [78].

Conclusions
On the basis of the literature reports discussed in this article, it is safe to conclude that the Petasis reaction is a highly efficient, atom-economical, one-pot, sustainable and waste-reducing approach.Synthetic methodologies based on the Petasis reaction have emerged as prestigious approaches to synthesize pharmaceutically relevant and structurally diverse scaffolds.This reaction proceeds well in the presence of different transition metal catalysts, Lewis acids, metal complexes bearing chiral ligands (BINOL), chitosan and ionic liquids.The functional group tolerance (substrate scope of this reaction) and diversity of the products obtained through this reaction are remarkable.Various groups have reported different alternate reaction protocols to achieve a Petasis reaction, and each methodology offers its own merits over the others, such as improved reaction yields, reduced reaction times, the recyclability of catalysts and mild reaction conditions.Albeit the extensive research conducted on Petasis reactions, the authors of this review article believe that there is still a great space to fill regarding the synthetic application of the Petasis reaction to produce natural products and drugs.Until now, only a few reports have been published involving the use of the Petasis reaction toward obtaining natural products.Moreover, the development of more and more alternate green/environmentally friendly reaction conditions for Petasis reactions are also needed at this time.

Conclusions
On the basis of the literature reports discussed in this article, it is safe to conclude that the Petasis reaction is a highly efficient, atom-economical, one-pot, sustainable and waste-reducing approach.Synthetic methodologies based on the Petasis reaction have emerged as prestigious approaches to synthesize pharmaceutically relevant and structurally diverse scaffolds.This reaction proceeds well in the presence of different transition metal catalysts, Lewis acids, metal complexes bearing chiral ligands (BINOL), chitosan and ionic liquids.The functional group tolerance (substrate scope of this reaction) and diversity of the products obtained through this reaction are remarkable.Various groups have reported different alternate reaction protocols to achieve a Petasis reaction, and each methodology offers its own merits over the others, such as improved reaction yields, reduced reaction times, the recyclability of catalysts and mild reaction conditions.Albeit the extensive research conducted on Petasis reactions, the authors of this review article believe that there is still a great space to fill regarding the synthetic application of the Petasis reaction to produce natural products and drugs.Until now, only a few reports have been published involving the use of the Petasis reaction toward obtaining natural products.Moreover, the development of more and more alternate green/environmentally friendly reaction conditions for Petasis reactions are also needed at this time.