# Synthesis and Reactions of Five-Membered Heterocycles Using Phase Transfer Catalyst (PTC) Techniques

Authors: Ahmed M. El-Sayed; Omyma A. Abd Allah; Ahmed M. M. El-Saghier; Shaaban K. Mohamed
Journal: Journal of Chemistry
 (2014)

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## Abstract

Phase transfer catalysts (PTCs) have been widely used for the synthesis of organic compounds particularly in both liquid-liquid and solid-liquid heterogeneous reaction mixtures. They are known to accelerate reaction rates by facilitating formation of interphase transfer of species and making reactions between reagents in two immiscible phases possible. Application of PTC instead of traditional technologies for industrial processes of organic synthesis provides substantial benefits for the environment. On the basis of numerous reports it is evident that phase-transfer catalysis is the most efficient way for generation and reactions of many active intermediates. In this review we report various uses of PTC in syntheses and reactions of five-membered heterocycles compounds and their multifused rings.


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## Body

## 1. Introduction

Organic synthesis is an essential way to get chemical products having practical applications such as pharmaceuticals, plant protection agents, dyes, photographic sensitizers, and monomers. Transformations of starting materials into desired final products usually require number of chemical operations in which additional reagents, catalysts, and solvents are employed. Thus, during any synthetic method, besides the desired products, many waste materials are produced because transformations of reactants into products are neither quantitative nor selective processes. This waste could be regenerated, destroyed, or disposed. This will lead to consuming much energy and creating heavy burden on the environment. Therefore it is of a great importance to develop and use synthetic methodologies that minimize or eliminate such problems. One of the most common and efficient methodologies that fulfill this requirement is employing phase-transfer catalyses techniques [1–4]. The most significant advantages of use of PTCs in industrial applications are [5](1)
elimination of organic solvents,
(2)
elimination of dangerous, inconvenient, and expensive reagents such as NaH and NaNH2,
(3)
increasing the reactivity and selectivity of the active species,
(4)
improving the yield and purity of products to the optimum records,
(5)
simplifying the whole synthetic process and making it safer and objective,
(6)
reducing industrial wastes and overall costs and saving energy which gives a positive impact on economic and environmental interests,
(7)
accelerating and performing mimic reactions in an efficient mode.


### 1.1. Fundamentals of Phase Transfer Catalysis (PTC)

First phase transfer catalysis was discovered by Jarrouse and Hebd in 1951 when they observed that the quaternary ammonium salt and benzyltriethylammonium chloride accelerated two-phase reaction of benzyl chloride with cyclohexanol (Figure1; (1)) and the two-phase alkylation reaction of phenylacetonitrile with benzyl chloride or ethyl chloride [6] (Figure 1; (2)).Figure 1In addition, numerous publications and patents [7–12] have been reported during the period of 1950–1965. PTCs techniques have been further developed by Makosza et al. for the purpose of obtaining more efficient and pure yield [13–16].


### 1.2. Mechanism of Phase Transfer Catalysis

All phase-transfer catalyzed reactions involve at least two steps:(1)
transfer of one reagent from its ground phase into the second phase as an intermediate,(2)
reaction of the transferred reagent with the nontransferred reagent, for example, the alkylation of phenylacetonitrile with alkyl halide using aqueous NaOH as a base and tetrabutylammonium halide (QX) as a catalyst can be formulated as shown in Figure2.Figure 2The concept of phase-transfer catalysis is not limited to anion transfer but is much more general, so that, in principle, one could also transfer cations, free radicals, or whole molecule. Phase transfer catalysis is classified as liquid-liquid, liquid-solid, liquid-gas, solid-gas, or solid-solid systems.


## 1.1. Fundamentals of Phase Transfer Catalysis (PTC)

First phase transfer catalysis was discovered by Jarrouse and Hebd in 1951 when they observed that the quaternary ammonium salt and benzyltriethylammonium chloride accelerated two-phase reaction of benzyl chloride with cyclohexanol (Figure1; (1)) and the two-phase alkylation reaction of phenylacetonitrile with benzyl chloride or ethyl chloride [6] (Figure 1; (2)).Figure 1In addition, numerous publications and patents [7–12] have been reported during the period of 1950–1965. PTCs techniques have been further developed by Makosza et al. for the purpose of obtaining more efficient and pure yield [13–16].


## 1.2. Mechanism of Phase Transfer Catalysis

All phase-transfer catalyzed reactions involve at least two steps:(1)
transfer of one reagent from its ground phase into the second phase as an intermediate,(2)
reaction of the transferred reagent with the nontransferred reagent, for example, the alkylation of phenylacetonitrile with alkyl halide using aqueous NaOH as a base and tetrabutylammonium halide (QX) as a catalyst can be formulated as shown in Figure2.Figure 2The concept of phase-transfer catalysis is not limited to anion transfer but is much more general, so that, in principle, one could also transfer cations, free radicals, or whole molecule. Phase transfer catalysis is classified as liquid-liquid, liquid-solid, liquid-gas, solid-gas, or solid-solid systems.


## 2. Application of Phase Transfer Catalysis in Synthesis of Five-Membered Ring of Heterocyclic Compounds

### 2.1. Synthesis of Five-Membered Ring Heterocycles Containing One Heteroatom

Treatment of anilinomethylenemalononitrile1with ethyl chloroacetate, chloroaceta-mide, phenacyl chloride, or diethyl bromomalonate in 1 : 1 : 1 molar ratio (dioxan/K2CO3/tetrabutylammonium bromide (TBAB)) afforded the corresponding substituted pyrroles 2a–cand 3, respectively [17] (Figure 3).Figure 3The catalytic cycle which explains the reaction pathway can be simplified as in Scheme1.Scheme 1A simple and convenient synthesis of 2-amino-1-aryl-5-oxo-4,5-dihydro-1H-pyrrole-3-carbonitriles 6was achieved by reaction of N-aryl-2-chloroacetamide 4and malononitrile 5under solid-liquid PTC condition (CH3CN/K2CO3/18-crown-6) at room temperature [18] (Figure 4).Figure 43-Amino-4-ethoxycarbonyl-1-phenyl-5-thioxo-2,5-dihydro-2-pyrrolidene malononitrile9a was prepared via reaction of malononitrile 5, phenyl isothiocyanate 7, and ethoxymethylenemalononitrile 8a in 1 : 1 : 1 molar ratio under the PTC mixture of dioxan/K2CO3/(TBAB). Replacing of ethyl ethoxymethylenecyanoacetate 8b with 8a gave ethyl[3-amino-4-ethoxy-carbonyl-1-phenyl-5-thioxo-2,5-dihydro-2-pyrrolidene]cyanoacetate 9band 10under the same experimental conditions [19] (Figure 5).Figure 5Moreover, the reaction of ethyl cyanoacetate11with phenyl isothiocyante 7and ethoxymethylenemalononitrile 8aor ethyl ethoxymethylenecyanoacetate 8bin 1 : 1 : 1 molar ratio under same PTC experimental conditions afforded the corresponding pyrrole derivatives 12a, b, and 13[19] (Figure 6).Figure 6Reaction of methyl 2,5-dibromopentanoate14with trichloroacetamide 15under solid-liquid technique (CH3CN/K2CO3/TEBACl) yielded methyl N-trichloroacetyl-2-pyrrolidine carboxylate 16[20] (Figure 7).Figure 7Substituted pyrrolidines19were synthesized via the 1,3-dipolar cycloaddition reaction between imino esters 17(derived from alanine and glycine with alkanes) and alkyl acrylate 18in a mixture of THF or toluene, KOH, and TBACl [21] (Figure 8).Figure 81,4-Di(malononitrilemethyleneamino)benzene20was allowed to react with ethyl chloroacetate, chloroacetamide, phenacyl chloride, or diethyl bromomalonate in 1 : 2 molar ratios under solid-liquid PTC technique to give the corresponding 1,4-bi(1-pyrrolyl) benzene derivatives 21a–cand22[17] (Figure 9).Figure 9Pyrrolidine derivatives24were obtained with thiophenes 25from the reaction of diethyl cyanomalonate 23with phenyl isothiocyanate 7and chloroacetonitrile or chloroacetamide using the PTC of (DMF/K2CO3/TBAB) [22] (Figure 10).Figure 10One-pot reaction of malononitrile5, carbon disulphide, and chloroacetamide in 1 : 1 : 1 molar ratio under solid-liquid PT catalysis (benzene/K2CO3/TBAB) has furnished 3-amino-2-carboxyamido-4-cyano-5-mercaptothiophene 26[23] (Figure 11). Also, treatment of malononitrile 5 with CS2 and ethyl chloroacetate under the same experimental conditions gave the corresponding thiophene derivative 27 [23] (Figure 11).Figure 11Different thiophene compounds (24and28–30)prepared from reaction of diethyl cyanomalonate 23 with carbon disulphide or phenyl isothiocyanate 7 along with different active halocompounds under solid-liquid phase condition (dioxan/K2CO3/TBAB) have been reported by Abd Allah and El-Sayed [22] (Figure 12).Figure 122-Thiophenylidenes31–33 were obtained through the reaction of either malononitrile 5 or ethyl cyanoacetate 11 with carbon disulphide along with ethoxymethylenemalononitrile 8a or ethyl ethoxymethylenecyanoacetate 8b using liquid-solid technique (dioxan/K2CO3/TBAB) [19] (Figure 13).Figure 13In this reaction, the yield of products was found to be a temperature dependent. Thus, at low temperature (40°C) it affords the aminothiophene derivative32ain high yield while at high temperature hydroxythiophene 32b or 33b was the solely product but in low yield.The reaction of pyridosultam34 with 3-chloropropyl thiocyanate under the experimental condition (toluene/aq. NaOH/TBAB) yielded the corresponding dihydrothiophene derivative 35[24] (Figure 14).Figure 144-Amino-5-cyano-2-hydroxy-3-furancarboxylic acid37and compound 38 were synthesized by treating 1-phenyl-3,5-pyrazolinedione 36 with bromomalononitrile under solid-liquid condition (dioxan/K2CO3/TBAB) (Figure 15) [25].Figure 15The reaction pathway for the formation of unexpected compound37was assumed to proceed via catalytic hydrolysis of compound 38 into the furan derivative 37and phenyl hydrazine [25] (Figure 16).Figure 16Condensation of salicylaldehyde39 and its derivatives with various esters of chloroacetic acids 40 in the presence of TBAB led to the synthesis of benzo[b]furans 41 under solventless and microwave irradiation technique [26] (Figure 17).Figure 17Liquid-liquid PTC reaction of 4-chlorobutyronitrile42 with nonenolizable aldehydes 43 via sequence of an addition cyclization reaction gave tetrahydrofuran-3-carbonitrile derivative 44 [27] (Figure 18).Figure 18Fused bis-aroylbenzodifurans46 have been synthesized by condensing 2,4-diacetyl resorcinol 45 with various p-substituted phenacyl bromides [28] (Figure 19).Figure 19Methyl or ethyl 3-amino-4-arylthiophenes-2-carboxylates48a–f were synthesized by Thorpe reaction through the treatment of 3-hydroxy-2-arylacrylonitriles 47a–fand methyl or ethyl thioglycolates with hydrochloric acid by using different PTC conditions (solid-liquid or liquid-liquid). The solid-liquid PTC conditions using 18-crown-6 along with potassium hydroxide as a catalyst are the method with excellent yields. The reactions were carried out in acetonitrile at RT [29] (Figure 20).Figure 20In Japp-Klingemann reaction the indole derivatives52 have been prepared as indicated in Figure 21. The addition of a suitable PTC catalyst to the reaction could significantly improve the reaction process. Firstly, aryl amines 49 were diazotized and reacted under alkaline conditions ethyl 2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-oxobutanoate50 using PTC-promoted Japp-Klingemann reaction to form the ring-opened aryl hydrazones 51. These aryl hydrazones were cyclized and converted into the corresponding indole derivatives 52 by adding hydrochloric acid in ethanol [30] (Figure 21).Figure 21Synthesis of dimethyl phosphinyl substituted tetra-hydropyrroles55 via 1,3-cycloaddition reaction of the azomethine53to electron deficient alkenes such as α,β-unsaturated ketones (e.g., benzylideneacetophenone 54), esters, and nitriles took place in high yield and low diastereoselectivity in phase-transfer catalysis conditions (solid potassium carbonate, triethylbenzylammonium chloride (TEBA)) in acetonitrile as a solvent [31] (Figure 22).Figure 22When Schiff base53and ethyl cinnamate 56 reacted under different phase-transfer catalysis conditions (10 equivalents of aqueous NaOH (50%)/TEBA/DMSO), the ester of pyrrolidinecarboxylic acid 57has not been formed; instead the acid itself58 was obtained as a mixture of two diastereoisomers [31] (Figure 23).Figure 23


### 2.2. Synthesis of Five-Membered Ring Heterocycles Containing Two Heteroatoms

(4Z)-4-(4-amino-1,3-dithiol-2-ylidene)-5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one derivative 60was the product of a reaction of 3-methyl-1-phenyl-2-pyrazoline-5-one 59with CS2 and chloroacetonitrile in equimolar ratio under solid-liquid technique (benzene/K2CO3/TBAB) [23] (Figure 24).Figure 24Similarly, 1-phenyl-3,5-pyrazolidinedione36 was treated with CS2 and ethyl chloroacetate under the same condition (benzene/K2CO3/TBAB) to give the corresponding (4Z)-4-(4-oxo-1,3-dithiolan-2-ylidene)-1-phenylpyrazolidine-3,5-dione 61 [25] (Figure 25).Figure 25The addition reaction of ethyl 3,4-diamino-5-cyanothieno[2,3-b]thiophene-2-carboxylate62to carbon disulfide, followed by cyclization reaction through the treatment with chloroacetonitrile or ethyl chloroacetate under PTC conditions (K2CO3, TBAB, dioxane), furnished 3,4-bis(4-amino-2-thioxo-1,3-thiazol-3(2H)-yl)-5-propanoylthieno[2,3-b]thiophene-2-carbonitrile 63 and 3,4-bis(4-oxo-2-thioxo-1,3-thiazolidin-3-yl)-5-propanoylthieno[2,3-b]thiophene-2-carbonitrile 64, in satisfactory yields [32] (Figure 26).Figure 26Moreover, the addition reaction of compound62 to carbon disulfide followed by cycloalkylation reaction with 1,2-dibromoethane, at 1 : 1 : 1 molar ratio under same PTC conditions, afforded the corresponding bis-1,3-dithiolan-2-ylidene 65[32] (Figure 27).Figure 27Treatment of triazepene compound66 with dibromides using liquid-liquid condition (benzene/NaOH/TBAB) furnished pyrazole derivatives 67a, b[33] (Figure 28).Figure 281,3-Dipolar cycloaddition of various substituted nitrilimines68to the appropriate alkenyl dipolarophiles 69 in aqueous media and in presence of a surfactant afforded a number of 1-aryl-5-substituted-4,5-dihydropyrazoles 70 [34] (Figure 29).Figure 29Preparation of 5-substituted oxazoles74 or imidazoles 75 was achieved by reaction of p-tolylsulphonylmethyl isocyanide 71 with aldehydes 72 R1CH=NR2 or 73 (R1, R2 = substituted phenyl, heteroaryl, and alkyl) under liquid-liquid condition [35, 36] (Figure 30).Figure 30The interaction of 3-chloro-3-methyl-1-butyne76 with 4,6-dimethyl-5-arylazo-2-thiopyrimidine 77 under liquid-liquid phase (benzene/aq. KOH/BTEACl) afforded 4,6-dimethyl-5-[2-(2-methylprop-1-enyl)-1H-benzimidazol-1-yl]pyrimidinyl-(5H)-thiones 78[37] (Figure 31).Figure 31Reaction of 5-phenylmethylene thiohydantoin79 with 1,2-dibromoethane 80under liquid-liquid conditions (benzene/aq. NaOH/TBAB) afforded 2,3-dihydro-6-phenylmethylene-5-oxo-imidazo[2,3-b]thiazole 81[38] (Figure 32).Figure 32A variety of 4-thiazolidinone derivatives83a–g were successfully synthesized via in situ formation of ketene-N,S-acetals 82a–g which in turn was reacted with ethyl chloroethyl acetate, chloroacetamide, or chloroacetyl chloride followed by ring closure to afford the desired 4-thiazolidinones 83a–g [39] (Figure 33).Figure 33One of the medicinal applications for PTC techniques is synthesis of sibenadet hydrochloride87which is a potent drug used for treatment of chronic obstructive pulmonary disease. This bioactive molecule was synthesized by O-alkylation of phenylethanol 84with the alkyl bromide 85under PTC condition to form the alkylated product 86 in 97% yield. Reaction of 86 with benzothiazole derivative led to formation of the desired product 86 [40] (Figure 34).Figure 34Treatment of an equimolar amount of 2-mercaptoquinazolin-4(3H)-one 88and dihalocompounds such as 1,2-dibromoethane and chloroacetyl chloride underwent S- and N-cyclo-alkylation by using PTC conditions, giving 2,3-di-hydro-5H-[1,3]thiazolo[2,3-b]quinazolin-5-one 89 and 5H-[1,3]-thiazolo-[2,3-b]quinazoline-3,5(2H)-dione 90, respectively [41] (Figure 35).Figure 35The PTC reaction of 3-phenyl-2-thiohydantoin91 with dihalocompounds, namely, ethylene dibromide or 1,3-dibromopropane, with CS2, yielded 1,3-dithioxane derivative92a or 5-(1,3-dithian-2-ylidene)-3-phenyl-2-thioxoimidazolidin-4-one derivative 92b, respectively [42] (Figure 36).Figure 36Treatment of the thiourea93 and urea 94derivatives with ethyl bromoacetate under PTC condition using TBAB as a catalyst and benzene/anhydrous K2CO3 as liquid-solid phases gave imidazolidinediones 95a,bvia ring closure pathway [43] (Figure 37).Figure 37


### 2.3. Synthesis of Five-Membered Ring Heterocycles Containing Three Heteroatoms

Alkylation of (2Z,5Z)-5-benzylidene-2-(hydroxyimino)imidazolidin-4-one 96 with methylene bromide in benzene/aq. NaOH in presence of TBAB as a catalyst gave 2-phenyl-2,3-dihydro-6-phenylmethylene-5-oxo-imidazo[2,1-c]-1,2,4-triazole 97. On the other hand, alkylation of the oxime derivative of 5-phenylmethylene thiohydantoin 98with methylene bromide gave 3-(1H)-6-phenylmethylene-5-oxo-imidazo[2,1-c]-1,2,4-oxadiazoles 99a,b[38] (Figure 38).Figure 38Anastrozole101 which acts as selective aromatase inhibitor and is employed effectively in treatment of advanced breast cancer in postmenopausal women has been synthesized in good yield by methylation reaction of 3,5-bis(cyanomethyl)toluene 100, using methyl chloride and 50% aq. NaOH/TEBA as a PTC condition [40] (Figure 39).Figure 39


### 2.4. Synthesis of Five-Membered Ring Heterocycles Containing Four Heteroatoms

5-Alkyl and 5-arylthiotetrazoles104 were synthesized in good yield from reaction of alkyl(aryl)thiocyanates 102 with azide 103under PTC conditions [44] (Figure 40).Figure 40Functionally substituted tetrazoles have been synthesized from the corresponding N,N′,N′′-triarylbenzene-1,3,5-tricarboxamides105via sequential transformation of these compounds into imidoyl chlorides and treatment of the latter with sodium azide under conditions of phase-transfer catalysis. As a result, a number of heterocyclic structures 106a–106econtaining three tetrazole rings have been isolated [45] (Figure 41).Figure 41


## 2.1. Synthesis of Five-Membered Ring Heterocycles Containing One Heteroatom

Treatment of anilinomethylenemalononitrile1with ethyl chloroacetate, chloroaceta-mide, phenacyl chloride, or diethyl bromomalonate in 1 : 1 : 1 molar ratio (dioxan/K2CO3/tetrabutylammonium bromide (TBAB)) afforded the corresponding substituted pyrroles 2a–cand 3, respectively [17] (Figure 3).Figure 3The catalytic cycle which explains the reaction pathway can be simplified as in Scheme1.Scheme 1A simple and convenient synthesis of 2-amino-1-aryl-5-oxo-4,5-dihydro-1H-pyrrole-3-carbonitriles 6was achieved by reaction of N-aryl-2-chloroacetamide 4and malononitrile 5under solid-liquid PTC condition (CH3CN/K2CO3/18-crown-6) at room temperature [18] (Figure 4).Figure 43-Amino-4-ethoxycarbonyl-1-phenyl-5-thioxo-2,5-dihydro-2-pyrrolidene malononitrile9a was prepared via reaction of malononitrile 5, phenyl isothiocyanate 7, and ethoxymethylenemalononitrile 8a in 1 : 1 : 1 molar ratio under the PTC mixture of dioxan/K2CO3/(TBAB). Replacing of ethyl ethoxymethylenecyanoacetate 8b with 8a gave ethyl[3-amino-4-ethoxy-carbonyl-1-phenyl-5-thioxo-2,5-dihydro-2-pyrrolidene]cyanoacetate 9band 10under the same experimental conditions [19] (Figure 5).Figure 5Moreover, the reaction of ethyl cyanoacetate11with phenyl isothiocyante 7and ethoxymethylenemalononitrile 8aor ethyl ethoxymethylenecyanoacetate 8bin 1 : 1 : 1 molar ratio under same PTC experimental conditions afforded the corresponding pyrrole derivatives 12a, b, and 13[19] (Figure 6).Figure 6Reaction of methyl 2,5-dibromopentanoate14with trichloroacetamide 15under solid-liquid technique (CH3CN/K2CO3/TEBACl) yielded methyl N-trichloroacetyl-2-pyrrolidine carboxylate 16[20] (Figure 7).Figure 7Substituted pyrrolidines19were synthesized via the 1,3-dipolar cycloaddition reaction between imino esters 17(derived from alanine and glycine with alkanes) and alkyl acrylate 18in a mixture of THF or toluene, KOH, and TBACl [21] (Figure 8).Figure 81,4-Di(malononitrilemethyleneamino)benzene20was allowed to react with ethyl chloroacetate, chloroacetamide, phenacyl chloride, or diethyl bromomalonate in 1 : 2 molar ratios under solid-liquid PTC technique to give the corresponding 1,4-bi(1-pyrrolyl) benzene derivatives 21a–cand22[17] (Figure 9).Figure 9Pyrrolidine derivatives24were obtained with thiophenes 25from the reaction of diethyl cyanomalonate 23with phenyl isothiocyanate 7and chloroacetonitrile or chloroacetamide using the PTC of (DMF/K2CO3/TBAB) [22] (Figure 10).Figure 10One-pot reaction of malononitrile5, carbon disulphide, and chloroacetamide in 1 : 1 : 1 molar ratio under solid-liquid PT catalysis (benzene/K2CO3/TBAB) has furnished 3-amino-2-carboxyamido-4-cyano-5-mercaptothiophene 26[23] (Figure 11). Also, treatment of malononitrile 5 with CS2 and ethyl chloroacetate under the same experimental conditions gave the corresponding thiophene derivative 27 [23] (Figure 11).Figure 11Different thiophene compounds (24and28–30)prepared from reaction of diethyl cyanomalonate 23 with carbon disulphide or phenyl isothiocyanate 7 along with different active halocompounds under solid-liquid phase condition (dioxan/K2CO3/TBAB) have been reported by Abd Allah and El-Sayed [22] (Figure 12).Figure 122-Thiophenylidenes31–33 were obtained through the reaction of either malononitrile 5 or ethyl cyanoacetate 11 with carbon disulphide along with ethoxymethylenemalononitrile 8a or ethyl ethoxymethylenecyanoacetate 8b using liquid-solid technique (dioxan/K2CO3/TBAB) [19] (Figure 13).Figure 13In this reaction, the yield of products was found to be a temperature dependent. Thus, at low temperature (40°C) it affords the aminothiophene derivative32ain high yield while at high temperature hydroxythiophene 32b or 33b was the solely product but in low yield.The reaction of pyridosultam34 with 3-chloropropyl thiocyanate under the experimental condition (toluene/aq. NaOH/TBAB) yielded the corresponding dihydrothiophene derivative 35[24] (Figure 14).Figure 144-Amino-5-cyano-2-hydroxy-3-furancarboxylic acid37and compound 38 were synthesized by treating 1-phenyl-3,5-pyrazolinedione 36 with bromomalononitrile under solid-liquid condition (dioxan/K2CO3/TBAB) (Figure 15) [25].Figure 15The reaction pathway for the formation of unexpected compound37was assumed to proceed via catalytic hydrolysis of compound 38 into the furan derivative 37and phenyl hydrazine [25] (Figure 16).Figure 16Condensation of salicylaldehyde39 and its derivatives with various esters of chloroacetic acids 40 in the presence of TBAB led to the synthesis of benzo[b]furans 41 under solventless and microwave irradiation technique [26] (Figure 17).Figure 17Liquid-liquid PTC reaction of 4-chlorobutyronitrile42 with nonenolizable aldehydes 43 via sequence of an addition cyclization reaction gave tetrahydrofuran-3-carbonitrile derivative 44 [27] (Figure 18).Figure 18Fused bis-aroylbenzodifurans46 have been synthesized by condensing 2,4-diacetyl resorcinol 45 with various p-substituted phenacyl bromides [28] (Figure 19).Figure 19Methyl or ethyl 3-amino-4-arylthiophenes-2-carboxylates48a–f were synthesized by Thorpe reaction through the treatment of 3-hydroxy-2-arylacrylonitriles 47a–fand methyl or ethyl thioglycolates with hydrochloric acid by using different PTC conditions (solid-liquid or liquid-liquid). The solid-liquid PTC conditions using 18-crown-6 along with potassium hydroxide as a catalyst are the method with excellent yields. The reactions were carried out in acetonitrile at RT [29] (Figure 20).Figure 20In Japp-Klingemann reaction the indole derivatives52 have been prepared as indicated in Figure 21. The addition of a suitable PTC catalyst to the reaction could significantly improve the reaction process. Firstly, aryl amines 49 were diazotized and reacted under alkaline conditions ethyl 2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-oxobutanoate50 using PTC-promoted Japp-Klingemann reaction to form the ring-opened aryl hydrazones 51. These aryl hydrazones were cyclized and converted into the corresponding indole derivatives 52 by adding hydrochloric acid in ethanol [30] (Figure 21).Figure 21Synthesis of dimethyl phosphinyl substituted tetra-hydropyrroles55 via 1,3-cycloaddition reaction of the azomethine53to electron deficient alkenes such as α,β-unsaturated ketones (e.g., benzylideneacetophenone 54), esters, and nitriles took place in high yield and low diastereoselectivity in phase-transfer catalysis conditions (solid potassium carbonate, triethylbenzylammonium chloride (TEBA)) in acetonitrile as a solvent [31] (Figure 22).Figure 22When Schiff base53and ethyl cinnamate 56 reacted under different phase-transfer catalysis conditions (10 equivalents of aqueous NaOH (50%)/TEBA/DMSO), the ester of pyrrolidinecarboxylic acid 57has not been formed; instead the acid itself58 was obtained as a mixture of two diastereoisomers [31] (Figure 23).Figure 23


## 2.2. Synthesis of Five-Membered Ring Heterocycles Containing Two Heteroatoms

(4Z)-4-(4-amino-1,3-dithiol-2-ylidene)-5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one derivative 60was the product of a reaction of 3-methyl-1-phenyl-2-pyrazoline-5-one 59with CS2 and chloroacetonitrile in equimolar ratio under solid-liquid technique (benzene/K2CO3/TBAB) [23] (Figure 24).Figure 24Similarly, 1-phenyl-3,5-pyrazolidinedione36 was treated with CS2 and ethyl chloroacetate under the same condition (benzene/K2CO3/TBAB) to give the corresponding (4Z)-4-(4-oxo-1,3-dithiolan-2-ylidene)-1-phenylpyrazolidine-3,5-dione 61 [25] (Figure 25).Figure 25The addition reaction of ethyl 3,4-diamino-5-cyanothieno[2,3-b]thiophene-2-carboxylate62to carbon disulfide, followed by cyclization reaction through the treatment with chloroacetonitrile or ethyl chloroacetate under PTC conditions (K2CO3, TBAB, dioxane), furnished 3,4-bis(4-amino-2-thioxo-1,3-thiazol-3(2H)-yl)-5-propanoylthieno[2,3-b]thiophene-2-carbonitrile 63 and 3,4-bis(4-oxo-2-thioxo-1,3-thiazolidin-3-yl)-5-propanoylthieno[2,3-b]thiophene-2-carbonitrile 64, in satisfactory yields [32] (Figure 26).Figure 26Moreover, the addition reaction of compound62 to carbon disulfide followed by cycloalkylation reaction with 1,2-dibromoethane, at 1 : 1 : 1 molar ratio under same PTC conditions, afforded the corresponding bis-1,3-dithiolan-2-ylidene 65[32] (Figure 27).Figure 27Treatment of triazepene compound66 with dibromides using liquid-liquid condition (benzene/NaOH/TBAB) furnished pyrazole derivatives 67a, b[33] (Figure 28).Figure 281,3-Dipolar cycloaddition of various substituted nitrilimines68to the appropriate alkenyl dipolarophiles 69 in aqueous media and in presence of a surfactant afforded a number of 1-aryl-5-substituted-4,5-dihydropyrazoles 70 [34] (Figure 29).Figure 29Preparation of 5-substituted oxazoles74 or imidazoles 75 was achieved by reaction of p-tolylsulphonylmethyl isocyanide 71 with aldehydes 72 R1CH=NR2 or 73 (R1, R2 = substituted phenyl, heteroaryl, and alkyl) under liquid-liquid condition [35, 36] (Figure 30).Figure 30The interaction of 3-chloro-3-methyl-1-butyne76 with 4,6-dimethyl-5-arylazo-2-thiopyrimidine 77 under liquid-liquid phase (benzene/aq. KOH/BTEACl) afforded 4,6-dimethyl-5-[2-(2-methylprop-1-enyl)-1H-benzimidazol-1-yl]pyrimidinyl-(5H)-thiones 78[37] (Figure 31).Figure 31Reaction of 5-phenylmethylene thiohydantoin79 with 1,2-dibromoethane 80under liquid-liquid conditions (benzene/aq. NaOH/TBAB) afforded 2,3-dihydro-6-phenylmethylene-5-oxo-imidazo[2,3-b]thiazole 81[38] (Figure 32).Figure 32A variety of 4-thiazolidinone derivatives83a–g were successfully synthesized via in situ formation of ketene-N,S-acetals 82a–g which in turn was reacted with ethyl chloroethyl acetate, chloroacetamide, or chloroacetyl chloride followed by ring closure to afford the desired 4-thiazolidinones 83a–g [39] (Figure 33).Figure 33One of the medicinal applications for PTC techniques is synthesis of sibenadet hydrochloride87which is a potent drug used for treatment of chronic obstructive pulmonary disease. This bioactive molecule was synthesized by O-alkylation of phenylethanol 84with the alkyl bromide 85under PTC condition to form the alkylated product 86 in 97% yield. Reaction of 86 with benzothiazole derivative led to formation of the desired product 86 [40] (Figure 34).Figure 34Treatment of an equimolar amount of 2-mercaptoquinazolin-4(3H)-one 88and dihalocompounds such as 1,2-dibromoethane and chloroacetyl chloride underwent S- and N-cyclo-alkylation by using PTC conditions, giving 2,3-di-hydro-5H-[1,3]thiazolo[2,3-b]quinazolin-5-one 89 and 5H-[1,3]-thiazolo-[2,3-b]quinazoline-3,5(2H)-dione 90, respectively [41] (Figure 35).Figure 35The PTC reaction of 3-phenyl-2-thiohydantoin91 with dihalocompounds, namely, ethylene dibromide or 1,3-dibromopropane, with CS2, yielded 1,3-dithioxane derivative92a or 5-(1,3-dithian-2-ylidene)-3-phenyl-2-thioxoimidazolidin-4-one derivative 92b, respectively [42] (Figure 36).Figure 36Treatment of the thiourea93 and urea 94derivatives with ethyl bromoacetate under PTC condition using TBAB as a catalyst and benzene/anhydrous K2CO3 as liquid-solid phases gave imidazolidinediones 95a,bvia ring closure pathway [43] (Figure 37).Figure 37


## 2.3. Synthesis of Five-Membered Ring Heterocycles Containing Three Heteroatoms

Alkylation of (2Z,5Z)-5-benzylidene-2-(hydroxyimino)imidazolidin-4-one 96 with methylene bromide in benzene/aq. NaOH in presence of TBAB as a catalyst gave 2-phenyl-2,3-dihydro-6-phenylmethylene-5-oxo-imidazo[2,1-c]-1,2,4-triazole 97. On the other hand, alkylation of the oxime derivative of 5-phenylmethylene thiohydantoin 98with methylene bromide gave 3-(1H)-6-phenylmethylene-5-oxo-imidazo[2,1-c]-1,2,4-oxadiazoles 99a,b[38] (Figure 38).Figure 38Anastrozole101 which acts as selective aromatase inhibitor and is employed effectively in treatment of advanced breast cancer in postmenopausal women has been synthesized in good yield by methylation reaction of 3,5-bis(cyanomethyl)toluene 100, using methyl chloride and 50% aq. NaOH/TEBA as a PTC condition [40] (Figure 39).Figure 39


## 2.4. Synthesis of Five-Membered Ring Heterocycles Containing Four Heteroatoms

5-Alkyl and 5-arylthiotetrazoles104 were synthesized in good yield from reaction of alkyl(aryl)thiocyanates 102 with azide 103under PTC conditions [44] (Figure 40).Figure 40Functionally substituted tetrazoles have been synthesized from the corresponding N,N′,N′′-triarylbenzene-1,3,5-tricarboxamides105via sequential transformation of these compounds into imidoyl chlorides and treatment of the latter with sodium azide under conditions of phase-transfer catalysis. As a result, a number of heterocyclic structures 106a–106econtaining three tetrazole rings have been isolated [45] (Figure 41).Figure 41


## 3. Synthesis of Fused Five-Membered Ring Heterocycles

Functionally substituted thieno(2,3-b)thiophenes107a,b were synthesized in a one-pot reaction of malononitrile 5, CS2, and α-halocarbethoxy or α-halonitrile electrophiles in 1 : 1 : 2 molar ratios using (benzene/K2CO3/TBAB) as a PTC condition [23] (Figure 42).Figure 42Another different thienothiophene109was synthesized via the reaction of acetylacetone 108with CS2 and ethyl chloroacetate in 1 : 1 : 2 molar ratio under the same experimental conditions [46] (Figure 43).Figure 43Thieno(2,3-b)pyrrole derivative110 was obtained by treating malononitrile 5 with phenyl isothiocyante 7 and ethyl chloroacetate in 1 : 1 : 2 molar ratio using (benzene/K2CO3/TBAB) as a phase transfer catalyst [23] (Figure 44).Figure 44Likewise, under the same conditions, 3-methyl-1-phenyl-2-pyrazoline-5-one63 was subjected to react with CS2 and chloroacetonitrile in 1 : 1 : 1 molar ratio where 6-cyano-4,6-dihydro-3-methyl-1-phenylthieno(3,4-c)pyrazol-4-thione 111 was obtained in good yield [23] (Figure 45).Figure 451-Phenyl-3,5-pyrazolinedione36was allowed to react with CS2 along with chloroacetonitrile or ethyl chloroacetate under the same conditions to give the corresponding thioxo-thienopyrazolone derivatives 112[25] (Figure 46).Figure 46Reaction of 4-hydroxydithiocoumarin113 with allyl bromide 114 under liquid-liquid technique (CH2Cl2/aq. NaOH/TBAB or TBACl) gave 2-methyl-2,3-dihydro-4H-thieno[2,3-b]benzothiopyran-4-one 115 [47] (Figure 47).Figure 47Treating of pyridazinium ylides116with N-phenylmaleimide, maleic and fumaric esters, resulted in the cycloadduct products 117–120 with high stereospecificity in the presence of KF and trioctylmethylammonium chloride or without solvent in the presence of aliquat 336 as phase transfer catalyst [48] (Figure 48).Figure 48Under solid-liquid technique (dioxan/K2CO3/TBAB), bis-thieno(1,8)naphthyridines 122 were prepared by reaction of 4,5-diamino-3,6-dicyano-(1,8)naphthyridine-2,7-dithiol 121with ethyl chloroacetate, chloroacetonitrile, phenacyl bromide, or chloroacetamide in 1 : 2 molar ratio or from reaction of 4,5-diamino-2,7-dichloro-3,6-dicyano(1,8)naphthyridine 123 with two equivalents of ethyl mercaptoacetate [49] (Figure 49).Figure 49Similarly 4-amino-3,5-dicyano-2-mercapto-6-methylthiopyridine124was reacted with ethyl chloroacetate, chloroacetonitrile, phenacyl bromide, or chloroacetamide in 1 : 1 molar ratio using the same PTC condition to give the corresponding thieno(2,3-b)pyridines 125or pyrrolo(2,3-d)thieno(2,3-b)pyridines 126[49] (Figure 50).Figure 50Using solid-liquid technique (dioxan/K2CO3/TBAB), 2-ylidenemalononitrile and ethyl 2-ylidenecyanoacetate of both 2,3-dihydrobenzothiazole 127 and 2,3-dihydrobenzoxazole 128 were allowed to react with chloroacetonitrile, ethyl chloroacetate, or phenacyl bromide in equimolar ratio which afforded the corresponding substituted pyrrolo[2,1-b]benzothiazoles 129 or substituted pyrrolo[2,1-b]benzoxazoles 130, respectively [42]. Similarly, (3-amino-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)propanenitrile malononitrile 131a or ethyl 3-amino-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)propanoate 131b were treated under the same PTC conditions, where the corresponding pyrrolo[2,3-b]pyrrolo[1,2-f]benzoimidazoles 132 were obtained [50] (Figure 51).Figure 51Reaction of 2,7-dichloro-1,8-naphthyridine derivative133 with ethyl glycinate hydrochloride in 1 : 1 molar ratio under solid-liquid technique (dioxan/K2CO3/TBAB) afforded the corresponding bis-pyrrolo(1,8)naphthyridine derivative 134 [49] (Figure 52).Figure 52Thieno(2,3-b) thiopyran derivatives136 were obtained from reaction of the thiopyran derivative 135 with ethyl chloroacetate in 1 : 1 molar ratio (dioxan/K2CO3/TBAB), while on carrying out the same reaction under the same conditions but in 1 : 2 molar ratio gave the corresponding thienopyrrolothiopyran derivatives 137[51] (Figure 53).Figure 53Treatment of 3-amino-1-phenyl-2-pyrazoline-5-one138 with CS2 along with chloroacetonitrile, ethyl chloroacetate, or phenacyl bromide in 1 : 1 : 1 and 1 : 1 : 2 molar ratios using [dioxan/K2CO3/TBAB] as a PTC gave the corresponding thienopyrazoles 139–143, 145 and respectively, 144, 146and147, fused thiazines [52] (Figure 54).Figure 54Thieno(3,4-b)pyrrole derivative148 was obtained by reacting ethyl thiophene-2-ylidenecyanoacetate derivative 31b with phenacyl bromide in a heterogeneous mixture of (dioxan/K2CO3/TBAB) as a PTC [19] (Figure 55).Figure 55In the same manner, pyridin-2-ylidenemalononitriles149a,b were reacted with phenacyl bromide under the same reaction condition and yielded the corresponding thieno(2,3-b)pyridine derivatives 150a,b [18] (Figure 56).Figure 562,6-Dibenzoyl-5-methyl-3-(substituted styryl)benzo[1,2-b:5,4-b]difurans152were synthesized from reaction of cinnamoylbenzofurans 151with phenacyl bromide under liquid-liquid technique (benzene/aq. K2CO3/TBAHSO4) [53] (Figure 57).Figure 57Similarly, 2,6-dibenzoyl-3,5-distyrylbenzo(1,2-b:5,4′-b)difurans154were prepared by condensing substituted dichalcones 153with phenacyl bromide under the same preceding PTC conditions [54] (Figure 58).Figure 58Also, under the same PTC conditions, dibenzoylbenzodifurans156were obtained from the reaction of substituted resorcinols 155 with phenacyl bromide [55] (Figure 59).Figure 59Moreover, 2,6-diaroyl/naphthoyl-3,5-dialkyl/phenylbenzo[1,2-b:5,4-b′]difurans158 were synthesized by condensing 2,4-diacyl/diaroylresorcinols 157 with various p-substituted α-bromo ketones [56] (Figure 60).Figure 60Treatment of 3-methyl-1-phenyl-2-pyrazolin-5-one63with bromomalononitrile in 1 : 1 molar ratio yielded 5-amino-4-cyano-3-methyl-1-phenylfuro(2,3-c)pyrazoline 159 [23] (Figure 61).Figure 61Furo(1,5)benzodiazepin derivative161was obtained by reaction of 1,4-dimethyl-3H-(1,5)benzodiazepin-2-one 160with chloroacetonitrile under solid-liquid condition (dioxan/K2CO3/TBAB) [57] (Figure 62).Figure 62By reaction of 4-methyl-1,3-dihydro-2H-1-benzazepin-2-one162 with chloroacetonitrile or phenacyl bromide under the solid-liquid phase transfer catalyst (dioxan/K2CO3/TBAB), the corresponding pyrrolo[1,2-a](1,5)benzodiazepine 163was obtained [58] (Figure 63).Figure 63Synthesis of 2,6-di(1-acetyl-2-oxopropylidene)dithiolo[4,5-b:4′,5′-e]-4,8-benzoquinone166 was achieved in one-pot reaction under solid-liquid technique (benzene/K2CO3/TBAB) starting from acetylacetone, CS2 to give 165 which in turn reacted with tetrabromo p-benzo-quinone 164 in 2 : 1 molar ratio [59] (Figure 64).Figure 64Treatment of 4-arylidene-1-phenyl-3,5-pyrazolinediones167 with S,S-acetal derivatives using solid-liquid technique (dioxan/K2CO3/TBAB) yielded the corresponding pyrazolino-(1,3)-dithiolane derivatives 168 [25] (Figure 65).Figure 65Some condensed heterocyclic systems171 were obtained by reacting 3-phenyl-4-amino-s-triazole-5-thiol 169as a dianionic compound containing N and S poles with some di- and tetrahaloderivatives 170 as well as α-haloketones and α-halonitrile derivatives under solid-liquid technique [60] (Figure 66).Figure 662-Aminoprop-1-ene-1,1,3-tricarbonitrile172was reacted with CS2 or PhNCS along with 3-methyl-1-phenyl-2-pyrazoline-5-one 63or 2-iminothiazolidin-4-one 173(dioxan/K2CO3/TBAB) to give the corresponding fused pyrazoles 174 and thiazoles 175, respectively [61] (Figure 67).Figure 67The reaction of 1,3-dihydro-4-methyl(1,5)benzodiazepin-2-one176with chloroacetonitrile using solid-liquid technique (dioxan/K2CO3/TBAB) gave the corresponding oxazolo-(1,5)benzodiazepin derivative 177 [57] (Figure 68).Figure 68When 7-(methoxyimino)-4-methyl-2H-chromene-2,8-(7H)-dione 178 was treated with crotyltriphenylphosphonium chloride (CTPPCl) 179 (CH2Cl2/Li(OH)/CTPPCl), the corresponding chromeno-oxazolone 180 was obtained in which one of the reactants (CTPPCl) acts also as a catalyst [62] (Figure 69).Figure 69The triazepine181 was treated with 1,2-dibromoethane under liquid-liquid technique (benzene/aq. NaOH/BTEACl) to afford the corresponding 6-methyl-8-phenyl-2,3-dihydro[1,3]thiazolo[3,2-d][1,2,4]triazepine-5(6H)-thione 182 [33] (Figure 70).Figure 70


## 4. Synthesis of Spiro Five-Membered Ring Heterocycles

Synthesis of spirorhodanine heterocycles184–187 was achieved by treating 5,5-dibromo-3-phenyl-2-thioxo-1,3-thiazolidin-4-one 183with different bidentates or with mixture of CS2 and some active methylene compounds under solid-liquid condition (dioxan/K2CO3/TBAB) [63] (Figure 71).Figure 71Reaction of 4-ethoxymethylene-1-phenyl-3,5-pyrazolidinedione188with CS2 and malononitrile 5 or ethyl cyanoacetate 11 using solid-liquid technique (dioxan/K2CO3/TBAB) yielded the corresponding spiro-1,3-dithiolane derivatives 189[25] (Figure 72).Figure 721-Benzoyl-3,3-dibromo-4-phenyl-(1,5)benzodiazepin-2-one190was reacted with different dinucleophiles under PTC condition (dioxan/K2CO3/TBAB) to furnish the corresponding spiroheterocycles attached to benzodiazepine moiety 191–193 [64] (Figure 73).Figure 73


## 5. Uses of Phase Transfer Catalysis Techniques in Reactions of Five-Membered Heterocycles

### 5.1. Alkylation and Acylation

#### 5.1.1. N-Alkylation or Acylation

Diez-Barra et al. [65] studied the alkylation of pyrrole 194 by PTC technique in absence of the solvent. The study revealed that the N versus C ratio is not affected by the nature of the catalyst. The nature of the leaving groups have a significant influence where N-alkylation increases in the sequence I < Br < Cl < OTs (Figure 74).Figure 74N-alkyl pyrroliden-2,5-diones200[66, 67] were synthesized via reaction of pyrroliden-2,5-diones with different alkylating reagents under phase transfer catalysis condition (toluene/K2CO3/TBAHSO4) according to (Figure 75).Figure 75N-allylindoles203 were easily carried out via N-allylation of the proper indoles 201 with the suitable allyl halides 202. The reaction was accomplished in diethyl ether via a phase transfer process in which 18-crown-6 was employed as the transfer agent and t-BuOK as the base [68] (Figure 76).Figure 762-Substituted 1-allylpyrroles206a–c were easily prepared from reaction of 2-formylpyrrole or 2-acetylpyrrole 204 with either 3-chlorobut-1-ene 205aor 3-chloro-2-methylprop-1-ene 205b, respectively, under phase transfer conditions (toluene/NaOH/TBAHSO4) [69] (Figure 77).Figure 77Treatment of pyrroles204 with 1,2-dichloroethane in presence of 50% NaOH and TBAB as a catalyst yielded the corresponding N-chloroethyl-pyroles 207in excellent yield which was transformed into 1,2-divinylpyrroles 208 via its reaction with sodamide using solid-liquid technique (THF/NaNH2/CH3Ph3Br) [70] (Figure 78).Figure 78Synthesis of a series of N-alkylpyrrolidino[59]fullerenes was achieved via the combination of PTC without solvent and microwave irradiation technique. Thus, 2-phenylpyrrolidinofullerene209was treated with benzyl, p-nitrobenzyl, p-methyloxy-carbonylbenzyl, n-octyl, or allyl bromides in microwave oven in presence of K2CO3 and TBAB to yield the corresponding N-alkylpyrrolidino[59]fullerenes 210 [71] (Figure 79).Figure 791,3-Bis[2-(aryl)indol-1-yl]propanes213and 1,3-bis[3-(aryl)-5-(aryl)pyrazol-1-yl]-propanes 214 were prepared from reaction of appropriate 2-arylindoles 211and 4,5-dihydropyrazoles 212, respectively, with 1,3-dibromopropane, via liquid-liquid technique using TBAHS as a catalyst, benzene as the organic phase, and 50% KOH as an aq. phase [72] (Figure 80).Figure 80Indole-2-acetonitrile215 was treated with (CH3)2CO3 in a mixture of [DMF/TBAB/K2CO3] to afford 1-methylindole-2-acetonitrile 216a and 2-(1-methylindole-3-yl)propionitrile 216b [73] (Figure 81).Figure 81Alkylation of indole217, 2,3-dimethylindole 218 with chlorodifluromethane under liquid-liquid technique (CH2Cl2/aq. NaOH/BzTEACl) afforded the corresponding 1-alkylated derivatives 219 and 220, respectively [74] (Figure 82).Figure 82Barraja et al. heated 2-substituted-3-bromoindoles221 with excess of different nucleophiles, solid KOH, and dibenzo-18-crown as a phase transfer catalyst to afford the corresponding 3-substituted indoles 222 in a satisfactory increase of yield [75] (Figure 83).Figure 83Carbazole223 was alkylated with 1,6-dibromohexane in 1 : 1 molar ratio to give N-alkyl derivative 224 in a mixture of (benzene/NaOH/TBAB) [76] (Figure 84).Figure 84Alkylation of pyrazole225with cyclopentyl or cyclohexyl bromides without solvent with PTC system (KOH/TBAB) afforded the corresponding 1-cyclopentyl or 1-cyclohexylpyrazoles 226a, b, respectively. Likewise treatment of pyrazole with 1,2-dibromoethane in 1 : 1 or 2 : 1 molar ratio afforded 1-bromoethylpyrazole or 1,2 bispyrazolylethane 227, 228[76](Figure 85). Also, alkylation reaction of 1H-pyrazole 225with linear or branched alkyl halide in liquid-liquid PTC system gave 1-alkyl-1H-pyrazole 229[77] (Figure 85).Figure 85The reaction of 3-tert-butylpyrazole230with dibromomethane afforded bis(tert-butylpyrazol-1-yl)methane [CH2(3-t-BuPz)2]231. However, the reaction of 3-isopropylpyrazole 232with dibromomethane under the same condition yielded three isomers, namely, bis(5-isopropylpyrazol-1-yl)methane[CH2(5-isoPrPz)2] 233, (3-isopropylpyrazol-1-yl-5′-isopropylpyrazol-1′-yl)methane[CH2(3-iPrPz-5′-isoPrPz)2] 234, and bis(3-isopropylpyrazol-1-yl)methane[CH2(3-iPrPz)2] 235[78] (Figure 86).Figure 86N-Substituted-3,5-diarylpyrazolines237 and 238 were prepared via liquid-liquid system in (CHCl3 or benzene/aq. KOH/TBAB) using alkyl and allyl halides, respectively, as alkylating agents for pyrazoles 236 [79] (Figure 87).Figure 87N-Alkylation reactions of 4,9-dihydro-9-methyl-4,10,10-trioxo-1(2H)-pyrazolo[3,4-c][2,1]-benzothiazepine239with dimethyl sulphate, diethyl sulphate, benzyl bromide, benzyl chloride, phenacyl bromide, phenacyl chloride, or cyclohexyl bromide under the liquid-liquid PTC condition of (toluene/NaOH(25%)/BTEACl, TBAB, or TBAHSO4) produced 1- and 2-alkylated isomers240a, b. The ratios between these two isomers were calculated [80] (Figure 88).Figure 88A number of 4-substituted pyrazolo[3,4-d]pyrimidines241 have been reacted with (2-acetoxyethoxy)methyl bromide using liquid-liquid and solid-liquid techniques. The influences of the solvent and catalyst have been studied [81, 82] (Figure 89).Figure 89Imidazole243was alkylated with different alkyl halides under solid-liquid PTC in absence of solvent where the N-alkyl imidazoles 244aand imidazolium salts 244b were obtained [83] (Figure 90).Figure 901-Alkyl(C4–C14)imidazoles 245 were obtained from the alkylation of imidazole 243 with the appropriate n-bromoalkane via PTC technique (benzene/KOH/TBAI) [84] (Figure 91).Figure 911-Alkyl-2-methyl-2-imidazolines247 were obtained in good to excellent yields by alkylation of 2-methyl-2-imidazoline 246with organic halides in the absence of solvent [85] (Figure 92).Figure 92Using the PTC condition such as (CH2Cl2/KOH/TEBA), a mixture (1 : 1) of N-alkylated 5-nitroimidazoles 250a, b or 6-nitrobenzimidazoles 251a, b was obtained by the reaction of 5-nitroimidazoles 248 or 6-nitrobenzimidazoles 249with methyl iodide or benzyl chloride, respectively, in a satisfactory yield [86] (Figure 93).Figure 93Different imidazole compounds such as 2-methylimidazole252aand 2-methyl-4-nitro imidazole 252b were reacted with different alkyl bromides253 in an alkaline media, at reflux temperature and in the presence of tetraethylammonium iodide (TEAI) or TBAB as PTC and afforded 1-alkyl imidazole derivatives 254 which exhibited a variety of valuable pharmacological properties [87] (Figure 94).Figure 94N-Alkyl-2-acetylbenzimidazoles257 have been obtained in over 90% yield by alkylating 2-acetylbenzimidazole 256 using the PTC mixture of (CH3CN/K2CO3/TEBACl) at room temperature [88] (Figure 95).Figure 952-Phenylbenzimidazole258was alkylated with chlorodifluromethane under liquid-liquid condition (CH2Cl2/aq. NaOH/BzTEACl) to give 1-difluoromethyl-2-phenylbenz-imidazole 259 [75] (Figure 96).Figure 96The N-alkylated imidazole derivatives262 were achieved by treating compounds 260 with different alkyl bromide 261under PTC condition (TBAB/K2CO3/CH3CN) [89] (Figure 97).Figure 97Competitive N versus O benzylation of 5,5-dimethyl-3-isoxazolidinone263using (CH2Cl2/NaOH) using different PTC catalysts was studied. The ratio of N-/O-alkylations 264a/264b was 2/3 for most cases of catalysts [90] (Figure 98).Figure 98Alkylation of 1,2,4-triazole265 and benzotriazole 267 has been performed either in basic media under solvent free PTC conditions or in absence of base by conventional and microwave heating. Several parameters affecting the selectivity have been studied [91]. Arylation of 1H-1,2,3-benzotriazole 267with activated aryl halides in a medium of aromatic hydrocarbons under PTC condition using inorganic bases and acetyltrimethylammonium bromide as a phase transfer catalyst was studied. Both N(1)- and N(2)-arylated products 269a and 269b, respectively, have been isolated. Their ratio has depended on the nature of the employed base and the reactivity of arylating agent [92] (Figure 99).Figure 99Treatment of benzotriazole267with chlorodifluromethane under liquid-liquid conditions (CH2Cl2/aq. NaOH/BzTEACl) has afforded 1-(difluoromethyl)-1H-benzotriazole270[74] (Figure 100).Figure 100Reaction of 4-substituted-1,2,3-triazol271 with alkyl bromide 272 under basic condition using PTC Bu4NBr produced N-substituted 1,2,3-triazole derivatives 273a–c [93] (Figure 101).Figure 101The alkylation of 5-benzyl-1H-tetrazole 274 under liquid- liquid technique such as (CH2Cl2/aq. NaOH/BzTEACl) gave a mixture of 5-benzyl-1-difluoromethyl-1,2,3,5-tetrazole 275ain 23% and 4-benzyl-1-difluoromethyl-1,2,3,5-tetrazole 275bin 15% [74] (Figure 102).Figure 102A series of 5-alkylthio-1-aryltetrazoles277were prepared by alkylation reaction of the corresponding 1-aryltetrazole-5-thiols 276with alkyl bromides under solid-liquid PTC technique [94], whereas without solvent and also under PTC technique several N-p-nitrophenylazoles 279–288were synthesized by direct arylation of the corresponding azolo compound 278with p-fluoronitrobenzene [95], while the alkylation reaction of 1-aryltetrazol-5-ones 289with dibromoalkanes under both liquid-liquid and solid-liquid PTC systems provided a convenient route to prepare bis-tetrazolon derivatives 290and 4-bromoalkyl derivatives 291[96] (Figure 103).Figure 103N-Acetylated adenosine292 was alkylated with benzyl bromide, methyl iodide, or allyl bromide in the presence of tetrabutylammonium bromide as a PTC catalyst in CH2Cl2/NaOH to give the corresponding N-alkyl-6-N-acetyl adenosines293a, b [97] (Figure 104).Figure 104N-alkylation reaction of adenine294took place with different alkyl halides under the phase transfer conditions using microwave irradiation assistance [98] (Figure 105).Figure 1055-Aryloxymethyl-2-[(2-chlorophenyl)oxyacetylamido]-1,3,4-thiadiazoles280are synthesized from reaction of 2-chlorophenyloxyacetyl chloride 297with 5-aryloxymethyl-2-amino-1,3,4-thiadiazoles 296 under liquid-liquid condition using PEG-400 as a catalyst [99] (Figure 106).Figure 106N-Alkylation of 3-phenyl-2-thiohydantoin-5-arylidene derivative299 has been carried out by using monohalocompounds such as allyl bromide as an alkylating agent. The reaction was proceeded through nucleophilic displacement under PTC conditions of solid-liquid phases such as a mixture of anhydrous potassium carbonate, dioxane, and TBAB as a heterogeneous catalyst. The corresponding alkylated product 300was obtained in a good yield [42] (Figure 107).Figure 107Alkylation reaction of pyrazoles301–303 with 2-chloroethylamine under the condition of phase-transfer catalysis was carried out in a liquid-solid system using benzene as an organic solvent and BTEAC as a catalyst. Reaction between equimolar amounts of reactants led to poor yields (20–40%) of the alkylated products 304–306 due to concurrent dehydrochlorination of 2-chloroethylamine. The yield was considerably decreased in going from pyrazole (301) to 3,5 dimethylpyrazole (303) whereas the maximal yield of alkylated products (70–80%) was obtained by using one of the following ratios: pyrazole : NaOH : 2-chloroethylamine 1 : 2 : 2, 3-(5)methylpyrazole : NaOH : 2 chloroethylamine 1 : 3 : 3, or 3,5-dimethylpyrazole : NaOH : 2-chloroethylamine 1 : 5 : 5 [100] (Figure 108).Figure 108In the N-alkylation reaction of pyrazole, 3-(5)-methylpyrazole, and 3,5-dimethylpyrazole301–303 with dichloroethane (DCE), the dehydrochlorination of the obtained 1-(β-chloroethyl)pyrazoles has been carried out to give the corresponding products N-vinylpyrazoles 307–309 (Figure 9) in low yield. Attempts to carry out the reaction under standard conditions (water/benzene/NaOH/TEBAC) did not lead to the desired result. The yield of all products was sharply increased when benzene was replaced with an excess of dichloroethane. The reaction investigation showed that the ease of alkylation depends strongly on the basicity of the pyrazole. The introduction of an electron-donating substituent (e.g., Me) into the molecule of pyrazole 301 increases the electron density at the “pyrazole” nitrogen atoms. As a result, deprotonation was hindered and the base was consumed in elimination of dichloroethane. It must also be mentioned that a 5- to 7-folds excess of dichloroethane was necessary to obtain optimal yields on alkylation of compounds 301–303 [101] (Figure 109).Figure 109


#### 5.1.2. O-Alkylation or Acylation

2,5-Didodecyloxymethylfuran311 was obtained via alkylation of 2,5-dihydroxymethylfuran 310 with dodecyl bromide without solvent using (KOH/aliquat) as a catalyst, while alkylation of furfuryl alcohol 312 with 1,12-dibromododecane under the same PTC conditions produced the corresponding furanic diether 313 [102] (Figure 110).Figure 110Similarly, 2-furfuryl alcohol312 was subjected to react with alkyl dihalides 314 using (benzene/KOH/polyethylene glycol (PEG-400)) to yield the corresponding difurfuryl diethers 315 [102] (Figure 110).4-(benzyloxy)-2-[(2E)-but-2-en-1-yloxy]-5-methoxytetrahydrofuran-3-ol317 was obtained from benzylation of 2-O-methyl-5-O-crotyl-α,β-D-ribofuranoside 316 using benzyl bromide in aq. solution of NaOH/CH2Cl2 and TBAB as a catalyst [103] (Figure 111).Figure 111


#### 5.1.3. S-Alkylation

PTC alkylation of arylidene derivative318 using dihalocompounds such as ethylene dibromide or 1,3-dibromopropane afforded the thioalkylated dimers 319a, b, respectively, via s-alkylation pathway followed by dimerization reaction [42] (Figure 112).Figure 112


#### 5.1.4. C-Alkylation

Reaction of 2-thiono-N(m-tolyl)thiazolidin-4-one 320 with methyl bromide, ethyl bromide, chloroacetaldehyde, ethyl chloroacetate, diethyl malonate, acetyl chloride, ethyl chloroformate, or p-nitrobenzenediazonium tetrafluoroborate under solid-liquid system and using the heterogeneous mixture of (dioxan/K2CO3/TBAB) as a PTC yielded the corresponding 5-substituted thiazolidin-4-ones 321a–h and yielded the corresponding spiro thiazolidin-4-one derivatives 322 when reacted with 1,2-dibromoethane under the same PTC condition [104] (Figure 113).Figure 1134-Benzyl-2-phenyl-2-oxazoline-4-carboxylic acid tertbutyl ester324 was prepared via the alkylation of 2-phenyl-2-oxazoline-4-carboxylic acid tert-butyl ester 323 with benzyl bromide using (toluene/KOH(s)/Cinchona alkaloids) as a PTC [105] (Figure 114).Figure 1142-Thioxo-3,5,7-trisubstituted-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)pyrido[2,3-d]-pyrimidin-4(1H)-ones 327 have been prepared via phase transfer ribosylation of 2-thioxo-3,5,7-trisubstituted pyrido[2,3-d]pyrimidin-4(1H)-ones 325 with 2,3,5-tri-O-benzoyl-β-D-ribofuranosyl bromide 326 in biphase solvents such as CH2Cl2/50% aq. NaOH using TBAB as a catalyst [106] (Figure 115).Figure 115In the presence of dioxane as a solvent under PTC conditions, one-pot reaction of 3-phenyl-2-thiohydantoin91 with CS2 and halocompounds such as ethyl bromide or benzyl chloride afforded 5-[bis(ethylsulfanyl)methylidene]-2-(ethylsulfanyl)-3-phenyl-3,5-dihydro-4H-imidazol-4-one328a and 5-[bis(benzylsulfanyl)methylidene]-2-(benzylsulfanyl)-3-phenyl-3,5-dihydro-4H-imidazol-4-one328b, respectively [42] (Figure 116).Figure 116Acylation of imidazolones318 using chloroacetyl chloride under PTC conditions yielded the corresponding acylated arylidene derivative 329 [42] (Figure 117).Figure 117


#### 5.1.5. Miscellaneous Alkylation

5-Bromorhodanine derivative330 was effectively used as an alkylating agent for some mono- or dianionic moieties containing S, N, or O under solid-liquid phase transfer catalysis conditions. Thus, with 4-hydroxy-2-mercaptopyrimidine, where possible S, N, or O sites are available, the reaction afforded the S-substituted product. With 2-aminobenzothiazole or piperazine, the reaction yielded the corresponding N-substituted 331a, b or the disubstituted products 332 [104] (Figure 118).Figure 118In a plan to study C- versus O-alkylation of the pyrazoline derivatives, 3-methyl-1-phenyl-2-pyrazolin-5-one333 was treated under PTC condition with different bromoorganic compounds such as benzyl bromide, 1,3-dibromopropane, methyl bromoacetate, bromoacetaldehyde, or diethylacetal as alkylating agents either in the absence or the presence of carbon disulphide and afforded numerous of C- or O-alkylated derivatives334a–e,335a–e [107] (Figure 119).Figure 119Reaction of 6-hydroxy-3,4-dihydroquinoline337and 1-cyclohexyl-5-(4-bromo-butyl)-1,2,3,4-tetrazole 336 in a heterogeneous mixture of toluene/H2O, K2CO3 and TBACl as a catalyst gave 6-[4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)butoxyl]-3,4-dihydrocarbostyril 338 in 99% purity [108] (Figure 120).Figure 120


### 5.2. Sulphonylation

4,5-Dihydro-3,5-diaryl-1-(4-fluorophenylsulphonyl)pyrazoles341 and 2-aryl-1-(4-fluorophenylsulphonyl)indoles 343 were prepared from reaction of 4-fluorophenylsulphonyl chloride 339 with the appropriate 4,5-dihydro-3,5-diarylpyrazoles 340or 2-arylindoles 342, via solid-liquid phase (THF/KOH/TBAB) [107] (Figure 121).Figure 121N-Sulphonylation product346 was prepared through treating 2-chloro-6,6-difluro-1,3-dioxolo[4,5-f]benzimidazole 344 with 3,5-dimethylisoxazole-4-sulphonyl chloride 345 via PTC protocol (toluene/aq. K2CO3/TBAB) [109] (Figure 122).Figure 122


### 5.3. N-Carbonylation

Carbonyldiimidazole349 was prepared in 87% yield via reaction of imidazole 347with phosgene 348 under PTC condition (chlorobenzene/NaOH/tributylhexadecylphosphonium bromide (TBHDPB)) [110] (Figure 123).Figure 123


### 5.4. N-Phosphorylation

Reaction of 1,3-thiazolidin-2-one350 with S-sec-Bu-O-Et chlorophosphorothiolate 351 in the presence of NaOH and N-dodecyl-N-methylephedrinium bromide gave s-sec-Bu O-Et(2-oxo-3-thiazolidinyl) phosphothiolate 352 in 84% yield [111] (Figure 124).Figure 124


### 5.5. Elimination Reactions

β-Elimination of bromomethyl cyclic ketyl acetals 353 was carried out under solid-liquid phase (THF/ButOK/Aliquat 336) to prepare the corresponding cyclic ketene acetals 354 [112] (Figure 125).Figure 125Reaction of 6-chloro-2-chloromethyl-3-nitroimidazo[1,2-b]pyridazine355with 3 equivalents of nitroalkane anion derivative 356under liquid-liquid PTC protocol (CH2Cl2/H2O/TBA(OH)) gave 3-nitroimidazo[1,2-b]pyridazines 357bearing trisubstituted ethylenic double bond derivatives in a good yield [113] (Figure 126).Figure 126Vinylation of indole358 with ClCH2CH2Br was achieved under PTC condition (toluene/KOH/18-crown-6) and afforded the corresponding N-vinyl derivative 359. Similarly, under the same reaction conditions N,S-divinyl derivatives 362and 363 were prepared from 3-mercaptoindole 360 and 2-mercaptobenzimidazole 361, respectively [109] (Figure 127).Figure 127


### 5.6. Condensation Reactions

Arylidenethiazolidin-4-ones385 were synthesized from condensation reaction of 2-thiono-N-(m-tolyl)thiazolidin-4-one 384with aromatic or heteroaldehydes under solid-liquid PTC technique [104] (Figure 128).Figure 128


### 5.7. Addition Reactions

Reaction of 2-thioxo-N-(m-tolyl)thiazolidin-4-one 386 with formaldehyde or some arylidenemalononitriles via PTC technique (dioxane/K2CO3/TBAB) afforded the corresponding 5-hydroxymethyl derivative387 or Michael type adduct 388, respectively. While the addition reaction of cyanoacetamide to 5-(p-methoxybenzylidene)-2-thioxo-N-(m-tolyl)thiazolidin-4-one 389followed by condensation reaction under the same technique gave 7-anisyl-6-cyano-2-thioxo-3-(m-tolyl)thiazolo[4,5-b]pyridin-5-one 390 [104] (Figure 129).Figure 129


### 5.8. Ring Expansion

Treatment of 5-alkyl(aryl)-3H-pyrrolin-2-ones 391with dichlorocarbene using (CHCl3/NaOH/BTEAB) at 20–30°C afforded the intermediates 1-alkyl-6,6-dichloro-2-azabicyclo[3.1.0]hexan-3-ones which directly rearranged and dehydrochlorinated to give 6-alkyl(aryl)-1-phenyl-5-oxohydropyridin-2-ones 392 [110] (Figure 130).Figure 130Also, ring transformation of indole derivatives393has been induced by dichlorocarbene (aq. KOH/TBABSO4H) to produce 3-haloquinoline 394in a good yield. Also, under similar conditions, reaction of 3-formyl-2-(3-chloro-4-fluorophenyl)indole 395with dichlorocarbene gave 3-chloro-4-[2,2-dichloro-3-oxiranyl]-2-(3′-chloro-4′-fluoro-phenyl)quinoline 396. The evolved HCl gas has been eliminated during the reaction [111] (Figure 131).Figure 131


### 5.9. Ring Opening

Treatment of benzosultams400 with different disulphides under PTC technique (CH3CN/K2CO3/TBAHSO4) gave the corresponding 2-methylamino-benzaldehyde dithioacetals 401 [24] (Figure 132).Figure 132


## 5.1. Alkylation and Acylation

### 5.1.1. N-Alkylation or Acylation

Diez-Barra et al. [65] studied the alkylation of pyrrole 194 by PTC technique in absence of the solvent. The study revealed that the N versus C ratio is not affected by the nature of the catalyst. The nature of the leaving groups have a significant influence where N-alkylation increases in the sequence I < Br < Cl < OTs (Figure 74).Figure 74N-alkyl pyrroliden-2,5-diones200[66, 67] were synthesized via reaction of pyrroliden-2,5-diones with different alkylating reagents under phase transfer catalysis condition (toluene/K2CO3/TBAHSO4) according to (Figure 75).Figure 75N-allylindoles203 were easily carried out via N-allylation of the proper indoles 201 with the suitable allyl halides 202. The reaction was accomplished in diethyl ether via a phase transfer process in which 18-crown-6 was employed as the transfer agent and t-BuOK as the base [68] (Figure 76).Figure 762-Substituted 1-allylpyrroles206a–c were easily prepared from reaction of 2-formylpyrrole or 2-acetylpyrrole 204 with either 3-chlorobut-1-ene 205aor 3-chloro-2-methylprop-1-ene 205b, respectively, under phase transfer conditions (toluene/NaOH/TBAHSO4) [69] (Figure 77).Figure 77Treatment of pyrroles204 with 1,2-dichloroethane in presence of 50% NaOH and TBAB as a catalyst yielded the corresponding N-chloroethyl-pyroles 207in excellent yield which was transformed into 1,2-divinylpyrroles 208 via its reaction with sodamide using solid-liquid technique (THF/NaNH2/CH3Ph3Br) [70] (Figure 78).Figure 78Synthesis of a series of N-alkylpyrrolidino[59]fullerenes was achieved via the combination of PTC without solvent and microwave irradiation technique. Thus, 2-phenylpyrrolidinofullerene209was treated with benzyl, p-nitrobenzyl, p-methyloxy-carbonylbenzyl, n-octyl, or allyl bromides in microwave oven in presence of K2CO3 and TBAB to yield the corresponding N-alkylpyrrolidino[59]fullerenes 210 [71] (Figure 79).Figure 791,3-Bis[2-(aryl)indol-1-yl]propanes213and 1,3-bis[3-(aryl)-5-(aryl)pyrazol-1-yl]-propanes 214 were prepared from reaction of appropriate 2-arylindoles 211and 4,5-dihydropyrazoles 212, respectively, with 1,3-dibromopropane, via liquid-liquid technique using TBAHS as a catalyst, benzene as the organic phase, and 50% KOH as an aq. phase [72] (Figure 80).Figure 80Indole-2-acetonitrile215 was treated with (CH3)2CO3 in a mixture of [DMF/TBAB/K2CO3] to afford 1-methylindole-2-acetonitrile 216a and 2-(1-methylindole-3-yl)propionitrile 216b [73] (Figure 81).Figure 81Alkylation of indole217, 2,3-dimethylindole 218 with chlorodifluromethane under liquid-liquid technique (CH2Cl2/aq. NaOH/BzTEACl) afforded the corresponding 1-alkylated derivatives 219 and 220, respectively [74] (Figure 82).Figure 82Barraja et al. heated 2-substituted-3-bromoindoles221 with excess of different nucleophiles, solid KOH, and dibenzo-18-crown as a phase transfer catalyst to afford the corresponding 3-substituted indoles 222 in a satisfactory increase of yield [75] (Figure 83).Figure 83Carbazole223 was alkylated with 1,6-dibromohexane in 1 : 1 molar ratio to give N-alkyl derivative 224 in a mixture of (benzene/NaOH/TBAB) [76] (Figure 84).Figure 84Alkylation of pyrazole225with cyclopentyl or cyclohexyl bromides without solvent with PTC system (KOH/TBAB) afforded the corresponding 1-cyclopentyl or 1-cyclohexylpyrazoles 226a, b, respectively. Likewise treatment of pyrazole with 1,2-dibromoethane in 1 : 1 or 2 : 1 molar ratio afforded 1-bromoethylpyrazole or 1,2 bispyrazolylethane 227, 228[76](Figure 85). Also, alkylation reaction of 1H-pyrazole 225with linear or branched alkyl halide in liquid-liquid PTC system gave 1-alkyl-1H-pyrazole 229[77] (Figure 85).Figure 85The reaction of 3-tert-butylpyrazole230with dibromomethane afforded bis(tert-butylpyrazol-1-yl)methane [CH2(3-t-BuPz)2]231. However, the reaction of 3-isopropylpyrazole 232with dibromomethane under the same condition yielded three isomers, namely, bis(5-isopropylpyrazol-1-yl)methane[CH2(5-isoPrPz)2] 233, (3-isopropylpyrazol-1-yl-5′-isopropylpyrazol-1′-yl)methane[CH2(3-iPrPz-5′-isoPrPz)2] 234, and bis(3-isopropylpyrazol-1-yl)methane[CH2(3-iPrPz)2] 235[78] (Figure 86).Figure 86N-Substituted-3,5-diarylpyrazolines237 and 238 were prepared via liquid-liquid system in (CHCl3 or benzene/aq. KOH/TBAB) using alkyl and allyl halides, respectively, as alkylating agents for pyrazoles 236 [79] (Figure 87).Figure 87N-Alkylation reactions of 4,9-dihydro-9-methyl-4,10,10-trioxo-1(2H)-pyrazolo[3,4-c][2,1]-benzothiazepine239with dimethyl sulphate, diethyl sulphate, benzyl bromide, benzyl chloride, phenacyl bromide, phenacyl chloride, or cyclohexyl bromide under the liquid-liquid PTC condition of (toluene/NaOH(25%)/BTEACl, TBAB, or TBAHSO4) produced 1- and 2-alkylated isomers240a, b. The ratios between these two isomers were calculated [80] (Figure 88).Figure 88A number of 4-substituted pyrazolo[3,4-d]pyrimidines241 have been reacted with (2-acetoxyethoxy)methyl bromide using liquid-liquid and solid-liquid techniques. The influences of the solvent and catalyst have been studied [81, 82] (Figure 89).Figure 89Imidazole243was alkylated with different alkyl halides under solid-liquid PTC in absence of solvent where the N-alkyl imidazoles 244aand imidazolium salts 244b were obtained [83] (Figure 90).Figure 901-Alkyl(C4–C14)imidazoles 245 were obtained from the alkylation of imidazole 243 with the appropriate n-bromoalkane via PTC technique (benzene/KOH/TBAI) [84] (Figure 91).Figure 911-Alkyl-2-methyl-2-imidazolines247 were obtained in good to excellent yields by alkylation of 2-methyl-2-imidazoline 246with organic halides in the absence of solvent [85] (Figure 92).Figure 92Using the PTC condition such as (CH2Cl2/KOH/TEBA), a mixture (1 : 1) of N-alkylated 5-nitroimidazoles 250a, b or 6-nitrobenzimidazoles 251a, b was obtained by the reaction of 5-nitroimidazoles 248 or 6-nitrobenzimidazoles 249with methyl iodide or benzyl chloride, respectively, in a satisfactory yield [86] (Figure 93).Figure 93Different imidazole compounds such as 2-methylimidazole252aand 2-methyl-4-nitro imidazole 252b were reacted with different alkyl bromides253 in an alkaline media, at reflux temperature and in the presence of tetraethylammonium iodide (TEAI) or TBAB as PTC and afforded 1-alkyl imidazole derivatives 254 which exhibited a variety of valuable pharmacological properties [87] (Figure 94).Figure 94N-Alkyl-2-acetylbenzimidazoles257 have been obtained in over 90% yield by alkylating 2-acetylbenzimidazole 256 using the PTC mixture of (CH3CN/K2CO3/TEBACl) at room temperature [88] (Figure 95).Figure 952-Phenylbenzimidazole258was alkylated with chlorodifluromethane under liquid-liquid condition (CH2Cl2/aq. NaOH/BzTEACl) to give 1-difluoromethyl-2-phenylbenz-imidazole 259 [75] (Figure 96).Figure 96The N-alkylated imidazole derivatives262 were achieved by treating compounds 260 with different alkyl bromide 261under PTC condition (TBAB/K2CO3/CH3CN) [89] (Figure 97).Figure 97Competitive N versus O benzylation of 5,5-dimethyl-3-isoxazolidinone263using (CH2Cl2/NaOH) using different PTC catalysts was studied. The ratio of N-/O-alkylations 264a/264b was 2/3 for most cases of catalysts [90] (Figure 98).Figure 98Alkylation of 1,2,4-triazole265 and benzotriazole 267 has been performed either in basic media under solvent free PTC conditions or in absence of base by conventional and microwave heating. Several parameters affecting the selectivity have been studied [91]. Arylation of 1H-1,2,3-benzotriazole 267with activated aryl halides in a medium of aromatic hydrocarbons under PTC condition using inorganic bases and acetyltrimethylammonium bromide as a phase transfer catalyst was studied. Both N(1)- and N(2)-arylated products 269a and 269b, respectively, have been isolated. Their ratio has depended on the nature of the employed base and the reactivity of arylating agent [92] (Figure 99).Figure 99Treatment of benzotriazole267with chlorodifluromethane under liquid-liquid conditions (CH2Cl2/aq. NaOH/BzTEACl) has afforded 1-(difluoromethyl)-1H-benzotriazole270[74] (Figure 100).Figure 100Reaction of 4-substituted-1,2,3-triazol271 with alkyl bromide 272 under basic condition using PTC Bu4NBr produced N-substituted 1,2,3-triazole derivatives 273a–c [93] (Figure 101).Figure 101The alkylation of 5-benzyl-1H-tetrazole 274 under liquid- liquid technique such as (CH2Cl2/aq. NaOH/BzTEACl) gave a mixture of 5-benzyl-1-difluoromethyl-1,2,3,5-tetrazole 275ain 23% and 4-benzyl-1-difluoromethyl-1,2,3,5-tetrazole 275bin 15% [74] (Figure 102).Figure 102A series of 5-alkylthio-1-aryltetrazoles277were prepared by alkylation reaction of the corresponding 1-aryltetrazole-5-thiols 276with alkyl bromides under solid-liquid PTC technique [94], whereas without solvent and also under PTC technique several N-p-nitrophenylazoles 279–288were synthesized by direct arylation of the corresponding azolo compound 278with p-fluoronitrobenzene [95], while the alkylation reaction of 1-aryltetrazol-5-ones 289with dibromoalkanes under both liquid-liquid and solid-liquid PTC systems provided a convenient route to prepare bis-tetrazolon derivatives 290and 4-bromoalkyl derivatives 291[96] (Figure 103).Figure 103N-Acetylated adenosine292 was alkylated with benzyl bromide, methyl iodide, or allyl bromide in the presence of tetrabutylammonium bromide as a PTC catalyst in CH2Cl2/NaOH to give the corresponding N-alkyl-6-N-acetyl adenosines293a, b [97] (Figure 104).Figure 104N-alkylation reaction of adenine294took place with different alkyl halides under the phase transfer conditions using microwave irradiation assistance [98] (Figure 105).Figure 1055-Aryloxymethyl-2-[(2-chlorophenyl)oxyacetylamido]-1,3,4-thiadiazoles280are synthesized from reaction of 2-chlorophenyloxyacetyl chloride 297with 5-aryloxymethyl-2-amino-1,3,4-thiadiazoles 296 under liquid-liquid condition using PEG-400 as a catalyst [99] (Figure 106).Figure 106N-Alkylation of 3-phenyl-2-thiohydantoin-5-arylidene derivative299 has been carried out by using monohalocompounds such as allyl bromide as an alkylating agent. The reaction was proceeded through nucleophilic displacement under PTC conditions of solid-liquid phases such as a mixture of anhydrous potassium carbonate, dioxane, and TBAB as a heterogeneous catalyst. The corresponding alkylated product 300was obtained in a good yield [42] (Figure 107).Figure 107Alkylation reaction of pyrazoles301–303 with 2-chloroethylamine under the condition of phase-transfer catalysis was carried out in a liquid-solid system using benzene as an organic solvent and BTEAC as a catalyst. Reaction between equimolar amounts of reactants led to poor yields (20–40%) of the alkylated products 304–306 due to concurrent dehydrochlorination of 2-chloroethylamine. The yield was considerably decreased in going from pyrazole (301) to 3,5 dimethylpyrazole (303) whereas the maximal yield of alkylated products (70–80%) was obtained by using one of the following ratios: pyrazole : NaOH : 2-chloroethylamine 1 : 2 : 2, 3-(5)methylpyrazole : NaOH : 2 chloroethylamine 1 : 3 : 3, or 3,5-dimethylpyrazole : NaOH : 2-chloroethylamine 1 : 5 : 5 [100] (Figure 108).Figure 108In the N-alkylation reaction of pyrazole, 3-(5)-methylpyrazole, and 3,5-dimethylpyrazole301–303 with dichloroethane (DCE), the dehydrochlorination of the obtained 1-(β-chloroethyl)pyrazoles has been carried out to give the corresponding products N-vinylpyrazoles 307–309 (Figure 9) in low yield. Attempts to carry out the reaction under standard conditions (water/benzene/NaOH/TEBAC) did not lead to the desired result. The yield of all products was sharply increased when benzene was replaced with an excess of dichloroethane. The reaction investigation showed that the ease of alkylation depends strongly on the basicity of the pyrazole. The introduction of an electron-donating substituent (e.g., Me) into the molecule of pyrazole 301 increases the electron density at the “pyrazole” nitrogen atoms. As a result, deprotonation was hindered and the base was consumed in elimination of dichloroethane. It must also be mentioned that a 5- to 7-folds excess of dichloroethane was necessary to obtain optimal yields on alkylation of compounds 301–303 [101] (Figure 109).Figure 109


### 5.1.2. O-Alkylation or Acylation

2,5-Didodecyloxymethylfuran311 was obtained via alkylation of 2,5-dihydroxymethylfuran 310 with dodecyl bromide without solvent using (KOH/aliquat) as a catalyst, while alkylation of furfuryl alcohol 312 with 1,12-dibromododecane under the same PTC conditions produced the corresponding furanic diether 313 [102] (Figure 110).Figure 110Similarly, 2-furfuryl alcohol312 was subjected to react with alkyl dihalides 314 using (benzene/KOH/polyethylene glycol (PEG-400)) to yield the corresponding difurfuryl diethers 315 [102] (Figure 110).4-(benzyloxy)-2-[(2E)-but-2-en-1-yloxy]-5-methoxytetrahydrofuran-3-ol317 was obtained from benzylation of 2-O-methyl-5-O-crotyl-α,β-D-ribofuranoside 316 using benzyl bromide in aq. solution of NaOH/CH2Cl2 and TBAB as a catalyst [103] (Figure 111).Figure 111


### 5.1.3. S-Alkylation

PTC alkylation of arylidene derivative318 using dihalocompounds such as ethylene dibromide or 1,3-dibromopropane afforded the thioalkylated dimers 319a, b, respectively, via s-alkylation pathway followed by dimerization reaction [42] (Figure 112).Figure 112


### 5.1.4. C-Alkylation

Reaction of 2-thiono-N(m-tolyl)thiazolidin-4-one 320 with methyl bromide, ethyl bromide, chloroacetaldehyde, ethyl chloroacetate, diethyl malonate, acetyl chloride, ethyl chloroformate, or p-nitrobenzenediazonium tetrafluoroborate under solid-liquid system and using the heterogeneous mixture of (dioxan/K2CO3/TBAB) as a PTC yielded the corresponding 5-substituted thiazolidin-4-ones 321a–h and yielded the corresponding spiro thiazolidin-4-one derivatives 322 when reacted with 1,2-dibromoethane under the same PTC condition [104] (Figure 113).Figure 1134-Benzyl-2-phenyl-2-oxazoline-4-carboxylic acid tertbutyl ester324 was prepared via the alkylation of 2-phenyl-2-oxazoline-4-carboxylic acid tert-butyl ester 323 with benzyl bromide using (toluene/KOH(s)/Cinchona alkaloids) as a PTC [105] (Figure 114).Figure 1142-Thioxo-3,5,7-trisubstituted-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)pyrido[2,3-d]-pyrimidin-4(1H)-ones 327 have been prepared via phase transfer ribosylation of 2-thioxo-3,5,7-trisubstituted pyrido[2,3-d]pyrimidin-4(1H)-ones 325 with 2,3,5-tri-O-benzoyl-β-D-ribofuranosyl bromide 326 in biphase solvents such as CH2Cl2/50% aq. NaOH using TBAB as a catalyst [106] (Figure 115).Figure 115In the presence of dioxane as a solvent under PTC conditions, one-pot reaction of 3-phenyl-2-thiohydantoin91 with CS2 and halocompounds such as ethyl bromide or benzyl chloride afforded 5-[bis(ethylsulfanyl)methylidene]-2-(ethylsulfanyl)-3-phenyl-3,5-dihydro-4H-imidazol-4-one328a and 5-[bis(benzylsulfanyl)methylidene]-2-(benzylsulfanyl)-3-phenyl-3,5-dihydro-4H-imidazol-4-one328b, respectively [42] (Figure 116).Figure 116Acylation of imidazolones318 using chloroacetyl chloride under PTC conditions yielded the corresponding acylated arylidene derivative 329 [42] (Figure 117).Figure 117


### 5.1.5. Miscellaneous Alkylation

5-Bromorhodanine derivative330 was effectively used as an alkylating agent for some mono- or dianionic moieties containing S, N, or O under solid-liquid phase transfer catalysis conditions. Thus, with 4-hydroxy-2-mercaptopyrimidine, where possible S, N, or O sites are available, the reaction afforded the S-substituted product. With 2-aminobenzothiazole or piperazine, the reaction yielded the corresponding N-substituted 331a, b or the disubstituted products 332 [104] (Figure 118).Figure 118In a plan to study C- versus O-alkylation of the pyrazoline derivatives, 3-methyl-1-phenyl-2-pyrazolin-5-one333 was treated under PTC condition with different bromoorganic compounds such as benzyl bromide, 1,3-dibromopropane, methyl bromoacetate, bromoacetaldehyde, or diethylacetal as alkylating agents either in the absence or the presence of carbon disulphide and afforded numerous of C- or O-alkylated derivatives334a–e,335a–e [107] (Figure 119).Figure 119Reaction of 6-hydroxy-3,4-dihydroquinoline337and 1-cyclohexyl-5-(4-bromo-butyl)-1,2,3,4-tetrazole 336 in a heterogeneous mixture of toluene/H2O, K2CO3 and TBACl as a catalyst gave 6-[4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)butoxyl]-3,4-dihydrocarbostyril 338 in 99% purity [108] (Figure 120).Figure 120


## 5.1.1. N-Alkylation or Acylation

Diez-Barra et al. [65] studied the alkylation of pyrrole 194 by PTC technique in absence of the solvent. The study revealed that the N versus C ratio is not affected by the nature of the catalyst. The nature of the leaving groups have a significant influence where N-alkylation increases in the sequence I < Br < Cl < OTs (Figure 74).Figure 74N-alkyl pyrroliden-2,5-diones200[66, 67] were synthesized via reaction of pyrroliden-2,5-diones with different alkylating reagents under phase transfer catalysis condition (toluene/K2CO3/TBAHSO4) according to (Figure 75).Figure 75N-allylindoles203 were easily carried out via N-allylation of the proper indoles 201 with the suitable allyl halides 202. The reaction was accomplished in diethyl ether via a phase transfer process in which 18-crown-6 was employed as the transfer agent and t-BuOK as the base [68] (Figure 76).Figure 762-Substituted 1-allylpyrroles206a–c were easily prepared from reaction of 2-formylpyrrole or 2-acetylpyrrole 204 with either 3-chlorobut-1-ene 205aor 3-chloro-2-methylprop-1-ene 205b, respectively, under phase transfer conditions (toluene/NaOH/TBAHSO4) [69] (Figure 77).Figure 77Treatment of pyrroles204 with 1,2-dichloroethane in presence of 50% NaOH and TBAB as a catalyst yielded the corresponding N-chloroethyl-pyroles 207in excellent yield which was transformed into 1,2-divinylpyrroles 208 via its reaction with sodamide using solid-liquid technique (THF/NaNH2/CH3Ph3Br) [70] (Figure 78).Figure 78Synthesis of a series of N-alkylpyrrolidino[59]fullerenes was achieved via the combination of PTC without solvent and microwave irradiation technique. Thus, 2-phenylpyrrolidinofullerene209was treated with benzyl, p-nitrobenzyl, p-methyloxy-carbonylbenzyl, n-octyl, or allyl bromides in microwave oven in presence of K2CO3 and TBAB to yield the corresponding N-alkylpyrrolidino[59]fullerenes 210 [71] (Figure 79).Figure 791,3-Bis[2-(aryl)indol-1-yl]propanes213and 1,3-bis[3-(aryl)-5-(aryl)pyrazol-1-yl]-propanes 214 were prepared from reaction of appropriate 2-arylindoles 211and 4,5-dihydropyrazoles 212, respectively, with 1,3-dibromopropane, via liquid-liquid technique using TBAHS as a catalyst, benzene as the organic phase, and 50% KOH as an aq. phase [72] (Figure 80).Figure 80Indole-2-acetonitrile215 was treated with (CH3)2CO3 in a mixture of [DMF/TBAB/K2CO3] to afford 1-methylindole-2-acetonitrile 216a and 2-(1-methylindole-3-yl)propionitrile 216b [73] (Figure 81).Figure 81Alkylation of indole217, 2,3-dimethylindole 218 with chlorodifluromethane under liquid-liquid technique (CH2Cl2/aq. NaOH/BzTEACl) afforded the corresponding 1-alkylated derivatives 219 and 220, respectively [74] (Figure 82).Figure 82Barraja et al. heated 2-substituted-3-bromoindoles221 with excess of different nucleophiles, solid KOH, and dibenzo-18-crown as a phase transfer catalyst to afford the corresponding 3-substituted indoles 222 in a satisfactory increase of yield [75] (Figure 83).Figure 83Carbazole223 was alkylated with 1,6-dibromohexane in 1 : 1 molar ratio to give N-alkyl derivative 224 in a mixture of (benzene/NaOH/TBAB) [76] (Figure 84).Figure 84Alkylation of pyrazole225with cyclopentyl or cyclohexyl bromides without solvent with PTC system (KOH/TBAB) afforded the corresponding 1-cyclopentyl or 1-cyclohexylpyrazoles 226a, b, respectively. Likewise treatment of pyrazole with 1,2-dibromoethane in 1 : 1 or 2 : 1 molar ratio afforded 1-bromoethylpyrazole or 1,2 bispyrazolylethane 227, 228[76](Figure 85). Also, alkylation reaction of 1H-pyrazole 225with linear or branched alkyl halide in liquid-liquid PTC system gave 1-alkyl-1H-pyrazole 229[77] (Figure 85).Figure 85The reaction of 3-tert-butylpyrazole230with dibromomethane afforded bis(tert-butylpyrazol-1-yl)methane [CH2(3-t-BuPz)2]231. However, the reaction of 3-isopropylpyrazole 232with dibromomethane under the same condition yielded three isomers, namely, bis(5-isopropylpyrazol-1-yl)methane[CH2(5-isoPrPz)2] 233, (3-isopropylpyrazol-1-yl-5′-isopropylpyrazol-1′-yl)methane[CH2(3-iPrPz-5′-isoPrPz)2] 234, and bis(3-isopropylpyrazol-1-yl)methane[CH2(3-iPrPz)2] 235[78] (Figure 86).Figure 86N-Substituted-3,5-diarylpyrazolines237 and 238 were prepared via liquid-liquid system in (CHCl3 or benzene/aq. KOH/TBAB) using alkyl and allyl halides, respectively, as alkylating agents for pyrazoles 236 [79] (Figure 87).Figure 87N-Alkylation reactions of 4,9-dihydro-9-methyl-4,10,10-trioxo-1(2H)-pyrazolo[3,4-c][2,1]-benzothiazepine239with dimethyl sulphate, diethyl sulphate, benzyl bromide, benzyl chloride, phenacyl bromide, phenacyl chloride, or cyclohexyl bromide under the liquid-liquid PTC condition of (toluene/NaOH(25%)/BTEACl, TBAB, or TBAHSO4) produced 1- and 2-alkylated isomers240a, b. The ratios between these two isomers were calculated [80] (Figure 88).Figure 88A number of 4-substituted pyrazolo[3,4-d]pyrimidines241 have been reacted with (2-acetoxyethoxy)methyl bromide using liquid-liquid and solid-liquid techniques. The influences of the solvent and catalyst have been studied [81, 82] (Figure 89).Figure 89Imidazole243was alkylated with different alkyl halides under solid-liquid PTC in absence of solvent where the N-alkyl imidazoles 244aand imidazolium salts 244b were obtained [83] (Figure 90).Figure 901-Alkyl(C4–C14)imidazoles 245 were obtained from the alkylation of imidazole 243 with the appropriate n-bromoalkane via PTC technique (benzene/KOH/TBAI) [84] (Figure 91).Figure 911-Alkyl-2-methyl-2-imidazolines247 were obtained in good to excellent yields by alkylation of 2-methyl-2-imidazoline 246with organic halides in the absence of solvent [85] (Figure 92).Figure 92Using the PTC condition such as (CH2Cl2/KOH/TEBA), a mixture (1 : 1) of N-alkylated 5-nitroimidazoles 250a, b or 6-nitrobenzimidazoles 251a, b was obtained by the reaction of 5-nitroimidazoles 248 or 6-nitrobenzimidazoles 249with methyl iodide or benzyl chloride, respectively, in a satisfactory yield [86] (Figure 93).Figure 93Different imidazole compounds such as 2-methylimidazole252aand 2-methyl-4-nitro imidazole 252b were reacted with different alkyl bromides253 in an alkaline media, at reflux temperature and in the presence of tetraethylammonium iodide (TEAI) or TBAB as PTC and afforded 1-alkyl imidazole derivatives 254 which exhibited a variety of valuable pharmacological properties [87] (Figure 94).Figure 94N-Alkyl-2-acetylbenzimidazoles257 have been obtained in over 90% yield by alkylating 2-acetylbenzimidazole 256 using the PTC mixture of (CH3CN/K2CO3/TEBACl) at room temperature [88] (Figure 95).Figure 952-Phenylbenzimidazole258was alkylated with chlorodifluromethane under liquid-liquid condition (CH2Cl2/aq. NaOH/BzTEACl) to give 1-difluoromethyl-2-phenylbenz-imidazole 259 [75] (Figure 96).Figure 96The N-alkylated imidazole derivatives262 were achieved by treating compounds 260 with different alkyl bromide 261under PTC condition (TBAB/K2CO3/CH3CN) [89] (Figure 97).Figure 97Competitive N versus O benzylation of 5,5-dimethyl-3-isoxazolidinone263using (CH2Cl2/NaOH) using different PTC catalysts was studied. The ratio of N-/O-alkylations 264a/264b was 2/3 for most cases of catalysts [90] (Figure 98).Figure 98Alkylation of 1,2,4-triazole265 and benzotriazole 267 has been performed either in basic media under solvent free PTC conditions or in absence of base by conventional and microwave heating. Several parameters affecting the selectivity have been studied [91]. Arylation of 1H-1,2,3-benzotriazole 267with activated aryl halides in a medium of aromatic hydrocarbons under PTC condition using inorganic bases and acetyltrimethylammonium bromide as a phase transfer catalyst was studied. Both N(1)- and N(2)-arylated products 269a and 269b, respectively, have been isolated. Their ratio has depended on the nature of the employed base and the reactivity of arylating agent [92] (Figure 99).Figure 99Treatment of benzotriazole267with chlorodifluromethane under liquid-liquid conditions (CH2Cl2/aq. NaOH/BzTEACl) has afforded 1-(difluoromethyl)-1H-benzotriazole270[74] (Figure 100).Figure 100Reaction of 4-substituted-1,2,3-triazol271 with alkyl bromide 272 under basic condition using PTC Bu4NBr produced N-substituted 1,2,3-triazole derivatives 273a–c [93] (Figure 101).Figure 101The alkylation of 5-benzyl-1H-tetrazole 274 under liquid- liquid technique such as (CH2Cl2/aq. NaOH/BzTEACl) gave a mixture of 5-benzyl-1-difluoromethyl-1,2,3,5-tetrazole 275ain 23% and 4-benzyl-1-difluoromethyl-1,2,3,5-tetrazole 275bin 15% [74] (Figure 102).Figure 102A series of 5-alkylthio-1-aryltetrazoles277were prepared by alkylation reaction of the corresponding 1-aryltetrazole-5-thiols 276with alkyl bromides under solid-liquid PTC technique [94], whereas without solvent and also under PTC technique several N-p-nitrophenylazoles 279–288were synthesized by direct arylation of the corresponding azolo compound 278with p-fluoronitrobenzene [95], while the alkylation reaction of 1-aryltetrazol-5-ones 289with dibromoalkanes under both liquid-liquid and solid-liquid PTC systems provided a convenient route to prepare bis-tetrazolon derivatives 290and 4-bromoalkyl derivatives 291[96] (Figure 103).Figure 103N-Acetylated adenosine292 was alkylated with benzyl bromide, methyl iodide, or allyl bromide in the presence of tetrabutylammonium bromide as a PTC catalyst in CH2Cl2/NaOH to give the corresponding N-alkyl-6-N-acetyl adenosines293a, b [97] (Figure 104).Figure 104N-alkylation reaction of adenine294took place with different alkyl halides under the phase transfer conditions using microwave irradiation assistance [98] (Figure 105).Figure 1055-Aryloxymethyl-2-[(2-chlorophenyl)oxyacetylamido]-1,3,4-thiadiazoles280are synthesized from reaction of 2-chlorophenyloxyacetyl chloride 297with 5-aryloxymethyl-2-amino-1,3,4-thiadiazoles 296 under liquid-liquid condition using PEG-400 as a catalyst [99] (Figure 106).Figure 106N-Alkylation of 3-phenyl-2-thiohydantoin-5-arylidene derivative299 has been carried out by using monohalocompounds such as allyl bromide as an alkylating agent. The reaction was proceeded through nucleophilic displacement under PTC conditions of solid-liquid phases such as a mixture of anhydrous potassium carbonate, dioxane, and TBAB as a heterogeneous catalyst. The corresponding alkylated product 300was obtained in a good yield [42] (Figure 107).Figure 107Alkylation reaction of pyrazoles301–303 with 2-chloroethylamine under the condition of phase-transfer catalysis was carried out in a liquid-solid system using benzene as an organic solvent and BTEAC as a catalyst. Reaction between equimolar amounts of reactants led to poor yields (20–40%) of the alkylated products 304–306 due to concurrent dehydrochlorination of 2-chloroethylamine. The yield was considerably decreased in going from pyrazole (301) to 3,5 dimethylpyrazole (303) whereas the maximal yield of alkylated products (70–80%) was obtained by using one of the following ratios: pyrazole : NaOH : 2-chloroethylamine 1 : 2 : 2, 3-(5)methylpyrazole : NaOH : 2 chloroethylamine 1 : 3 : 3, or 3,5-dimethylpyrazole : NaOH : 2-chloroethylamine 1 : 5 : 5 [100] (Figure 108).Figure 108In the N-alkylation reaction of pyrazole, 3-(5)-methylpyrazole, and 3,5-dimethylpyrazole301–303 with dichloroethane (DCE), the dehydrochlorination of the obtained 1-(β-chloroethyl)pyrazoles has been carried out to give the corresponding products N-vinylpyrazoles 307–309 (Figure 9) in low yield. Attempts to carry out the reaction under standard conditions (water/benzene/NaOH/TEBAC) did not lead to the desired result. The yield of all products was sharply increased when benzene was replaced with an excess of dichloroethane. The reaction investigation showed that the ease of alkylation depends strongly on the basicity of the pyrazole. The introduction of an electron-donating substituent (e.g., Me) into the molecule of pyrazole 301 increases the electron density at the “pyrazole” nitrogen atoms. As a result, deprotonation was hindered and the base was consumed in elimination of dichloroethane. It must also be mentioned that a 5- to 7-folds excess of dichloroethane was necessary to obtain optimal yields on alkylation of compounds 301–303 [101] (Figure 109).Figure 109


## 5.1.2. O-Alkylation or Acylation

2,5-Didodecyloxymethylfuran311 was obtained via alkylation of 2,5-dihydroxymethylfuran 310 with dodecyl bromide without solvent using (KOH/aliquat) as a catalyst, while alkylation of furfuryl alcohol 312 with 1,12-dibromododecane under the same PTC conditions produced the corresponding furanic diether 313 [102] (Figure 110).Figure 110Similarly, 2-furfuryl alcohol312 was subjected to react with alkyl dihalides 314 using (benzene/KOH/polyethylene glycol (PEG-400)) to yield the corresponding difurfuryl diethers 315 [102] (Figure 110).4-(benzyloxy)-2-[(2E)-but-2-en-1-yloxy]-5-methoxytetrahydrofuran-3-ol317 was obtained from benzylation of 2-O-methyl-5-O-crotyl-α,β-D-ribofuranoside 316 using benzyl bromide in aq. solution of NaOH/CH2Cl2 and TBAB as a catalyst [103] (Figure 111).Figure 111


## 5.1.3. S-Alkylation

PTC alkylation of arylidene derivative318 using dihalocompounds such as ethylene dibromide or 1,3-dibromopropane afforded the thioalkylated dimers 319a, b, respectively, via s-alkylation pathway followed by dimerization reaction [42] (Figure 112).Figure 112


## 5.1.4. C-Alkylation

Reaction of 2-thiono-N(m-tolyl)thiazolidin-4-one 320 with methyl bromide, ethyl bromide, chloroacetaldehyde, ethyl chloroacetate, diethyl malonate, acetyl chloride, ethyl chloroformate, or p-nitrobenzenediazonium tetrafluoroborate under solid-liquid system and using the heterogeneous mixture of (dioxan/K2CO3/TBAB) as a PTC yielded the corresponding 5-substituted thiazolidin-4-ones 321a–h and yielded the corresponding spiro thiazolidin-4-one derivatives 322 when reacted with 1,2-dibromoethane under the same PTC condition [104] (Figure 113).Figure 1134-Benzyl-2-phenyl-2-oxazoline-4-carboxylic acid tertbutyl ester324 was prepared via the alkylation of 2-phenyl-2-oxazoline-4-carboxylic acid tert-butyl ester 323 with benzyl bromide using (toluene/KOH(s)/Cinchona alkaloids) as a PTC [105] (Figure 114).Figure 1142-Thioxo-3,5,7-trisubstituted-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)pyrido[2,3-d]-pyrimidin-4(1H)-ones 327 have been prepared via phase transfer ribosylation of 2-thioxo-3,5,7-trisubstituted pyrido[2,3-d]pyrimidin-4(1H)-ones 325 with 2,3,5-tri-O-benzoyl-β-D-ribofuranosyl bromide 326 in biphase solvents such as CH2Cl2/50% aq. NaOH using TBAB as a catalyst [106] (Figure 115).Figure 115In the presence of dioxane as a solvent under PTC conditions, one-pot reaction of 3-phenyl-2-thiohydantoin91 with CS2 and halocompounds such as ethyl bromide or benzyl chloride afforded 5-[bis(ethylsulfanyl)methylidene]-2-(ethylsulfanyl)-3-phenyl-3,5-dihydro-4H-imidazol-4-one328a and 5-[bis(benzylsulfanyl)methylidene]-2-(benzylsulfanyl)-3-phenyl-3,5-dihydro-4H-imidazol-4-one328b, respectively [42] (Figure 116).Figure 116Acylation of imidazolones318 using chloroacetyl chloride under PTC conditions yielded the corresponding acylated arylidene derivative 329 [42] (Figure 117).Figure 117


## 5.1.5. Miscellaneous Alkylation

5-Bromorhodanine derivative330 was effectively used as an alkylating agent for some mono- or dianionic moieties containing S, N, or O under solid-liquid phase transfer catalysis conditions. Thus, with 4-hydroxy-2-mercaptopyrimidine, where possible S, N, or O sites are available, the reaction afforded the S-substituted product. With 2-aminobenzothiazole or piperazine, the reaction yielded the corresponding N-substituted 331a, b or the disubstituted products 332 [104] (Figure 118).Figure 118In a plan to study C- versus O-alkylation of the pyrazoline derivatives, 3-methyl-1-phenyl-2-pyrazolin-5-one333 was treated under PTC condition with different bromoorganic compounds such as benzyl bromide, 1,3-dibromopropane, methyl bromoacetate, bromoacetaldehyde, or diethylacetal as alkylating agents either in the absence or the presence of carbon disulphide and afforded numerous of C- or O-alkylated derivatives334a–e,335a–e [107] (Figure 119).Figure 119Reaction of 6-hydroxy-3,4-dihydroquinoline337and 1-cyclohexyl-5-(4-bromo-butyl)-1,2,3,4-tetrazole 336 in a heterogeneous mixture of toluene/H2O, K2CO3 and TBACl as a catalyst gave 6-[4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)butoxyl]-3,4-dihydrocarbostyril 338 in 99% purity [108] (Figure 120).Figure 120


## 5.2. Sulphonylation

4,5-Dihydro-3,5-diaryl-1-(4-fluorophenylsulphonyl)pyrazoles341 and 2-aryl-1-(4-fluorophenylsulphonyl)indoles 343 were prepared from reaction of 4-fluorophenylsulphonyl chloride 339 with the appropriate 4,5-dihydro-3,5-diarylpyrazoles 340or 2-arylindoles 342, via solid-liquid phase (THF/KOH/TBAB) [107] (Figure 121).Figure 121N-Sulphonylation product346 was prepared through treating 2-chloro-6,6-difluro-1,3-dioxolo[4,5-f]benzimidazole 344 with 3,5-dimethylisoxazole-4-sulphonyl chloride 345 via PTC protocol (toluene/aq. K2CO3/TBAB) [109] (Figure 122).Figure 122


## 5.3. N-Carbonylation

Carbonyldiimidazole349 was prepared in 87% yield via reaction of imidazole 347with phosgene 348 under PTC condition (chlorobenzene/NaOH/tributylhexadecylphosphonium bromide (TBHDPB)) [110] (Figure 123).Figure 123


## 5.4. N-Phosphorylation

Reaction of 1,3-thiazolidin-2-one350 with S-sec-Bu-O-Et chlorophosphorothiolate 351 in the presence of NaOH and N-dodecyl-N-methylephedrinium bromide gave s-sec-Bu O-Et(2-oxo-3-thiazolidinyl) phosphothiolate 352 in 84% yield [111] (Figure 124).Figure 124


## 5.5. Elimination Reactions

β-Elimination of bromomethyl cyclic ketyl acetals 353 was carried out under solid-liquid phase (THF/ButOK/Aliquat 336) to prepare the corresponding cyclic ketene acetals 354 [112] (Figure 125).Figure 125Reaction of 6-chloro-2-chloromethyl-3-nitroimidazo[1,2-b]pyridazine355with 3 equivalents of nitroalkane anion derivative 356under liquid-liquid PTC protocol (CH2Cl2/H2O/TBA(OH)) gave 3-nitroimidazo[1,2-b]pyridazines 357bearing trisubstituted ethylenic double bond derivatives in a good yield [113] (Figure 126).Figure 126Vinylation of indole358 with ClCH2CH2Br was achieved under PTC condition (toluene/KOH/18-crown-6) and afforded the corresponding N-vinyl derivative 359. Similarly, under the same reaction conditions N,S-divinyl derivatives 362and 363 were prepared from 3-mercaptoindole 360 and 2-mercaptobenzimidazole 361, respectively [109] (Figure 127).Figure 127


## 5.6. Condensation Reactions

Arylidenethiazolidin-4-ones385 were synthesized from condensation reaction of 2-thiono-N-(m-tolyl)thiazolidin-4-one 384with aromatic or heteroaldehydes under solid-liquid PTC technique [104] (Figure 128).Figure 128


## 5.7. Addition Reactions

Reaction of 2-thioxo-N-(m-tolyl)thiazolidin-4-one 386 with formaldehyde or some arylidenemalononitriles via PTC technique (dioxane/K2CO3/TBAB) afforded the corresponding 5-hydroxymethyl derivative387 or Michael type adduct 388, respectively. While the addition reaction of cyanoacetamide to 5-(p-methoxybenzylidene)-2-thioxo-N-(m-tolyl)thiazolidin-4-one 389followed by condensation reaction under the same technique gave 7-anisyl-6-cyano-2-thioxo-3-(m-tolyl)thiazolo[4,5-b]pyridin-5-one 390 [104] (Figure 129).Figure 129


## 5.8. Ring Expansion

Treatment of 5-alkyl(aryl)-3H-pyrrolin-2-ones 391with dichlorocarbene using (CHCl3/NaOH/BTEAB) at 20–30°C afforded the intermediates 1-alkyl-6,6-dichloro-2-azabicyclo[3.1.0]hexan-3-ones which directly rearranged and dehydrochlorinated to give 6-alkyl(aryl)-1-phenyl-5-oxohydropyridin-2-ones 392 [110] (Figure 130).Figure 130Also, ring transformation of indole derivatives393has been induced by dichlorocarbene (aq. KOH/TBABSO4H) to produce 3-haloquinoline 394in a good yield. Also, under similar conditions, reaction of 3-formyl-2-(3-chloro-4-fluorophenyl)indole 395with dichlorocarbene gave 3-chloro-4-[2,2-dichloro-3-oxiranyl]-2-(3′-chloro-4′-fluoro-phenyl)quinoline 396. The evolved HCl gas has been eliminated during the reaction [111] (Figure 131).Figure 131


## 5.9. Ring Opening

Treatment of benzosultams400 with different disulphides under PTC technique (CH3CN/K2CO3/TBAHSO4) gave the corresponding 2-methylamino-benzaldehyde dithioacetals 401 [24] (Figure 132).Figure 132



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*Source: 163074-2014-02-25.xml*