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

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.


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][2][3][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 NaNH 2 , (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.

Mechanism of Phase-Transfer Catalysis.
All phasetransfer 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 Figure 2.
The 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.
In this reaction, the yield of products was found to be a temperature dependent.Thus, at low temperature (40 ∘ C) it affords the aminothiophene derivative 32a in high yield while at high temperature hydroxythiophene 32b or 33b was the solely product but in low yield.
The reaction pathway for the formation of unexpected compound 37 was assumed to proceed via catalytic hydrolysis of compound 38 into the furan derivative 37 and phenyl hydrazine [25] (Figure 16).Condensation of salicylaldehyde 39 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).
Methyl or ethyl 3-amino-4-arylthiophenes-2-carboxylates 48a-f were synthesized by Thorpe reaction through the treatment of 3-hydroxy-2-arylacrylonitriles 47a-f and 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).
When Schiff base 53 and ethyl cinnamate 56 reacted under different phase-transfer catalysis conditions (10 equivalents of aqueous NaOH (50%)/TEBA/DMSO), the ester of pyrrolidinecarboxylic acid 57 has not been formed;  instead the acid itself 58 was obtained as a mixture of two diastereoisomers [31] (Figure 23).
A variety of 4-thiazolidinone derivatives 83a-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 4thiazolidinones 83a-g [39] (Figure 33).
One of the medicinal applications for PTC techniques is synthesis of sibenadet hydrochloride 87 which is a potent drug used for treatment of chronic obstructive pulmonary disease.This bioactive molecule was synthesized by Oalkylation of phenylethanol 84 with the alkyl bromide 85 under 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).
Treatment of the thiourea 93 and urea 94 derivatives with ethyl bromoacetate under PTC condition using TBAB as a catalyst and benzene/anhydrous K 2 CO 3 as liquid-solid phases gave imidazolidinediones 95a, b via ring closure pathway [43] (Figure 37).
Anastrozole 101 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 3,5bis(cyanomethyl)toluene 100, using methyl chloride and 50% aq.NaOH/TEBA as a PTC condition [40] (Figure 39).
Functionally substituted tetrazoles have been synthesized from the corresponding N,N  ,N  -triarylbenzene-1,3,5tricarboxamides 105 via 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-106e containing three tetrazole rings have been isolated [45] (Figure 41).
Treating of pyridazinium ylides 116 with 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).

Uses of Phase Transfer Catalysis Techniques in Reactions of Five-Membered Heterocycles
N-allylindoles 203 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).
Alkylation of pyrazole 225 with cyclopentyl or cyclohexyl bromides without solvent with PTC system (KOH/
Alkylation of 1,2,4-triazole 265 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-1,2,3benzotriazole 267 with 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).Treatment of benzotriazole 267 with chlorodifluromethane under liquid-liquid conditions (CH 2 Cl 2 /aq.NaOH/ BzTEACl) has afforded 1-(difluoromethyl)-1H-benzotriazole 270 [74] (Figure 100).
N-alkylation reaction of adenine 294 took place with different alkyl halides under the phase transfer conditions using microwave irradiation assistance [98] (Figure 105).
N-Alkylation of 3-phenyl-2-thiohydantoin-5-arylidene derivative 299 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 300 was obtained in a good yield [42] (Figure 107).
In the N-alkylation reaction of pyrazole, 3-(5)-methylpyrazole, and 3,5-dimethylpyrazole 301-303 with dichloroethane (DCE), the dehydrochlorination of the obtained 1-(-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).
Acylation of imidazolones 318 using chloroacetyl chloride under PTC conditions yielded the corresponding acylated arylidene derivative 329 [42] (Figure 117).5.1.5.Miscellaneous Alkylation.5-Bromorhodanine derivative 330 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).

Abbreviations
First phase transfer catalysis was discovered by Jarrouse and Hebd in 1951 when they observed that the quaternary