Hindawi Publishing Corporation Journal of Chemistry Volume 2014, Article ID 163074, 47 pages http://dx.doi.org/10.1155/2014/163074

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

Ahmed M. El-Sayed,1 Omyma A. Abd Allah,1 Ahmed M. M. El-Saghier,1 and Shaaban K. Mohamed2,3

1 Department of Chemistry, Faculty of Science, Sohag University, Sohag 82524, Egypt 2 Chemistry and Environmental Division, Manchester Metropolitan University, Manchester M1 5GD, UK 3 Chemistry Department, Faculty of Science, Minia University, El-Minia 61519, Egypt

Correspondence should be addressed to Omyma A. Abd Allah; [email protected]

Received 1 May 2013; Revised 15 September 2013; Accepted 28 October 2013; Published 25 February 2014

Academic Editor: Jorge F. Fernandez-Sanchez

Copyright © 2014 Ahmed M. El-Sayed et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.

1. Introduction (1) elimination of organic solvents, Organic synthesis is an essential way to get chemical prod- (2) elimination of dangerous, inconvenient, and expen- ucts having practical applications such as pharmaceuti- sive reagents such as NaH and NaNH2, cals, plant protection agents, dyes, photographic sensitizers, (3) increasing the reactivity and selectivity of the active and monomers. Transformations of starting materials into species, desired final products usually require number of chemi- cal operations in which additional reagents, catalysts, and (4) improving the yield and purity of products to the solvents are employed. Thus, during any synthetic method, optimum records, besides the desired products, many waste materials are (5) simplifying the whole synthetic process and making produced because transformations of reactants into products it safer and objective, are neither quantitative nor selective processes. This waste (6) reducing industrial wastes and overall costs and sav- could be regenerated, destroyed, or disposed. This will lead ing energy which gives a positive impact on economic to consuming much energy and creating heavy burden on and environmental interests, the environment. Therefore it is of a great importance to develop and use synthetic methodologies that minimize (7) accelerating and performing mimic reactions in an or eliminate such problems. One of the most common efficient mode. and efficient methodologies that fulfill this requirement is employing phase-transfer catalyses techniques [1–4]. The 1.1. Fundamentals of Phase Transfer Catalysis (PTC). First most significant advantages of use of PTCs in industrial phase transfer catalysis was discovered by Jarrouse and Hebd applications are [5] in 1951 when they observed that the quaternary ammonium 2 Journal of Chemistry

OH OCH2Ph Cl PhCH2NEt3Cl + (1) NaOH CN

CN PhCH2NEt3Cl + C2H5Cl C2H5 NaOH (2)

Figure 1 − + PhCH2CN + NaOH PhCHCN Na + H2O org. int aq. − + + − − + PhCHCN Na + QX PhCHCN Q + NaX int org. org. aq.

− + Ph + − PhCHCN Q + R-X CHC N + QX org. org. R org. org.

Figure 2

NC NH2

ClCH2R N R Ph 2a–c

PhNH-CH = C(CN)2 R: a = CO2Et, b = CONH2, c = COPh

NC NH BrCH(COOEt)2 CO2Et

N CO2Et Ph 3

Figure 3 CN

PTC ArNHCOCH2Cl + CH2(CN)2 O NH N 2

Ar 45 6

Figure 4

salt and benzyltriethylammonium chloride accelerated two- 1.2. Mechanism of Phase-Transfer Catalysis. All phase- phasereactionofbenzylchloridewithcyclohexanol(Figure 1; transfer catalyzed reactions involve at least two steps: (1)) and the two-phase alkylation reaction of phenylacetoni- trile with benzyl chloride or ethyl chloride [6](Figure 1; (2)). (1) transfer of one reagent from its ground phase into the In addition, numerous publications and patents [7–12] second phase as an intermediate, have been reported during the period of 1950–1965. PTCs (2)reactionofthetransferredreagentwiththenon- techniques have been further developed by Makosza et al. for transferred reagent, for example, the alkylation of the purpose of obtaining more efficient and pure yield13 [ – phenylacetonitrile with alkyl halide using aqueous 16]. NaOH as a base and tetrabutylammonium halide Journal of Chemistry 3

K2CO3 solid surface

Ph NH CN CN Y NH2 Q Ph-N PhN CN HX + CN CN

XCH2Y QX HX Organic layer Y Y NQ

PhN Ph-N CN CN CN Y Q PhN CN CN

Scheme 1

(QX) as a catalyst can be formulated as shown in the PTC mixture of dioxan/K2CO3/(TBAB). Replacing Figure 2. of ethyl ethoxymethylenecyanoacetate 8b with 8a gave ethyl[3-amino-4-ethoxy-carbonyl-1-phenyl-5-thioxo-2,5-di- The concept of phase-transfer catalysis is not limited to hydro-2-pyrrolidene]cyanoacetate 9b and 10 under the same anion transfer but is much more general, so that, in principle, experimental conditions [19](Figure 5). one could also transfer cations, free radicals, or whole Moreover, the reaction of ethyl cyanoacetate 11 with molecule. Phase transfer catalysis is classified as liquid-liquid, phenyl isothiocyante 7 and ethoxymethylenemalononitrile liquid-solid, liquid-gas, solid-gas, or solid-solid systems. 8a or ethyl ethoxymethylenecyanoacetate 8b in1:1:1molar ratio under same PTC experimental conditions afforded 2. Application of Phase Transfer Catalysis the corresponding pyrrole derivatives 12a, b,and13 [19] in Synthesis of Five-Membered Ring of (Figure 6). Heterocyclic Compounds Reaction of methyl 2,5-dibromopentanoate 14 with tri- chloroacetamide 15 under solid-liquid technique (CH3CN/ 2.1. Synthesis of Five-Membered Ring Heterocycles Con- K2CO3/TEBACl) yielded methyl N-trichloroacetyl-2-pyr- taining One Heteroatom. Treatment of anilinomethylene- rolidine carboxylate 16 [20](Figure 7). malononitrile 1 with ethyl chloroacetate, chloroaceta-mide, Substituted pyrrolidines 19 were synthesized via the phenacyl chloride, or diethyl bromomalonate in 1 : 1 : 1 1,3-dipolar cycloaddition reaction between imino esters 17 molar ratio (dioxan/K2CO3/tetrabutylammonium bromide (TBAB)) afforded the corresponding substituted pyrroles 2a– (derived from alanine and glycine with alkanes) and alkyl c and 3,respectively[17](Figure 3). acrylate 18 in a mixture of THF or toluene, KOH, and TBACl [21](Figure 8). The catalytic cycle which explains the reaction pathway can be simplified as in Scheme 1. 1,4-Di(malononitrilemethyleneamino)benzene 20 was A simple and convenient synthesis of 2-amino-1-aryl-5- allowed to react with ethyl chloroacetate, chloroacetamide, oxo-4,5-dihydro-1H-pyrrole-3-carbonitriles 6 was achieved phenacyl chloride, or diethyl bromomalonate in 1 : 2 by reaction of N-aryl-2-chloroacetamide 4 and malononitrile molar ratios under solid-liquid PTC technique to give the 5 under solid-liquid PTC condition (CH3CN/K2CO3/18- corresponding 1,4-bi(1-pyrrolyl) benzene derivatives 21a–c crown-6) at room temperature [18](Figure 4). and 22 [17](Figure 9). 3-Amino-4-ethoxycarbonyl-1-phenyl-5-thioxo-2,5-dihy- Pyrrolidine derivatives 24 were obtained with thiophenes dro-2-pyrrolidene malononitrile 9a was prepared via reac- 25 from the reaction of diethyl cyanomalonate 23 with phenyl tion of malononitrile 5,phenylisothiocyanate7, and ethox- isothiocyanate 7 and chloroacetonitrile or chloroacetamide ymethylenemalononitrile 8a in 1:1:1 molar ratio under using the PTC of (DMF/K2CO3/TBAB) [22](Figure 10). 4 Journal of Chemistry

NC CN NC CN PTC CH2(CN)2 + PhNCS 57 S NH PhN SH Ph

NC NC NH PTC NH2 2 + CN EtOCH = C(CN) X CN S N PhN S X CN Ph 10 8a, b 9a, b

X: a = CN, b =COOEt

Figure 5

EtOOC CN PTC EtOOC CN CNCH2COOEt + PhNCS S NH PhN SH 11 7 Ph

EtOCH=C(CN)(COOEt) PTC PTC EtOCH=C(CN)2 8b 8a

EtOOC NH EtOOC NH 2 2 EtOOC NH2 + CN CN CN PhN S N S S N COOEt COOEt Ph Ph CN Hydrolysis 12b 12a H2O/K2CO3 −PhNH2

EtOOC NH2

CN O S COOEt 13

Figure 6

PTC Br(CH ) CH(Br)COOCH + Cl CCONH COOCH 2 3 3 3 2 N 3 14 15 COCCl3 16

Figure 7

One-potreactionofmalononitrile5,carbondisulphide, CS2 and ethyl chloroacetate under the same experimental and chloroacetamide in 1 : 1 : 1 molar ratio under solid- conditions gave the corresponding thiophene derivative 27 liquid PT catalysis (benzene/K2CO3/TBAB) has furnished [23](Figure 11). 3-amino-2-carboxyamido-4-cyano-5-mercaptothiophene 26 Different thiophene compounds (24 and 28–30)prepared [23](Figure 11). Also, treatment of malononitrile 5 with from reaction of diethyl cyanomalonate 23 with carbon Journal of Chemistry 5

R R O + − N COOR + − R N X COOR N COOR + 4 R4N X R1 N R H 1 KOH KOH 17 18 19

R1 O

Figure 8

R R H2N NH2 2ClCH2R N N NC NC CN NC HN NH CN 21a–c PTC R = CO Et, CONH , COPh 20 CN 2 2 CO Et EtO C EtO2C 2 2 CO2Et HN NH 2BrCH(CO2Et)2 N N NC CN 22

Figure 9

Et O Et O Et O CN CN O O Et O O Et O O Et + PhNCS PTC NC O PhN O PhNH O H SH SH

PTC XCH2Y

X Z X Z EtO2C EtO2C + S Y N PhN S Y Ph 25 24a–c

X = CO2Et, Y = CN, Z = NH2 24a, b: X= CO2Et, Y = CN, Z = NH2 24c: X = CN, Y = CONH2, Z = OH

Figure 10

CN H2N PTC CH2(CN)2 + CS2 + ClCH2CONH2 5 H2NOC S SH 26

H2N CN PTC CH2(CN)2 + CS2 + ClCH2COOEt EtO C SCH CO Et 5 2 S 2 2 27

Figure 11 6 Journal of Chemistry

CS2 PTC O O O XCH2Y NC PTC O S SH

O O CO2Et O EtO2C NH 2 NC OH NC PTC EtO2C + O S S S S O O S S Y Y O NC Y 28a–c 29a–c O H a, Y = COPh, b, Y = CN, c, Y = CONH2 23 CN PhNCS CO2Et EtO2C CO2Et 7 EtO2C CN PTC PhN SH S NH Ph NC OH X X Z XCH Y Z 2 EtO2C + + EtO2C EtO2C PTC PhN S COPh PhN S Y S N Y Ph 30 25a–c 24

24a, b, 25a-b; X = CO2C2H5, Y = CN, Z = NH2

24c, 25c; X = CO2C2H5, Y = CONH2, Z = NH2

Figure 12

disulphide or phenyl isothiocyanate 7 along with different Condensation of salicylaldehyde 39 and its derivatives active halocompounds under solid-liquid phase condition with various esters of chloroacetic acids 40 in the pres- (dioxan/K2CO3/TBAB) have been reported by Abd Allah and ence of TBAB led to the synthesis of benzo[b]furans 41 El-Sayed [22](Figure 12). under solventless and microwave irradiation technique [26] 2-Thiophenylidenes 31–33 were obtained through the (Figure 17). reaction of either malononitrile 5 or ethyl cyanoacetate 11 Liquid-liquid PTC reaction of 4-chlorobutyronitrile 42 with carbon disulphide along with ethoxymethylenemal- with nonenolizable aldehydes 43 via sequence of an addi- ononitrile 8a or ethyl ethoxymethylenecyanoacetate 8b tion cyclization reaction gave tetrahydrofuran-3-carbonitrile using liquid-solid technique (dioxan/K2CO3/TBAB) [19] derivative 44 [27](Figure 18). (Figure 13). Fused bis-aroylbenzodifurans 46 have been synthesized In this reaction, the yield of products was found to be a by condensing 2,4-diacetyl resorcinol 45 with various p- ∘ temperature dependent. Thus, at low temperature (40 C) it substituted phenacyl bromides [28](Figure 19). affords the aminothiophene derivative 32a in high yield while Methyl or ethyl 3-amino-4-arylthiophenes-2-carbox- at high temperature hydroxythiophene 32b or 33b was the ylates 48a–f were synthesized by Thorpe reaction through solely product but in low yield. the treatment of 3-hydroxy-2-arylacrylonitriles 47a–f and The reaction of pyridosultam 34 with 3-chloropropyl methyl or ethyl thioglycolates with hydrochloric acid by using different PTC conditions (solid-liquid or liquid-liquid). thiocyanate under the experimental condition (toluene/aq. The solid-liquid PTC conditions using 18-crown-6 along NaOH/TBAB) yielded the corresponding dihydrothiophene with potassium hydroxide as a catalyst are the method with derivative 35 [24](Figure 14). excellent yields. The reactions were carried out in acetonitrile 4-Amino-5-cyano-2-hydroxy-3-furancarboxylic acid 37 at RT [29](Figure 20). and compound 38 were synthesized by treating 1-phenyl-3,5- In Japp-Klingemann reaction the indole derivatives 52 pyrazolinedione 36 with bromomalononitrile under solid- have been prepared as indicated in Figure 21. The addition liquid condition (dioxan/K2CO3/TBAB) (Figure 15)[25]. of a suitable PTC catalyst to the reaction could signifi- The reaction pathway for the formation of unexpected cantly improve the reaction process. Firstly, aryl amines compound 37 was assumed to proceed via catalytic hydrolysis 49 were diazotized and reacted under alkaline conditions of compound 38 into the furan derivative 37 and phenyl ethyl 2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3- hydrazine [25](Figure 16). oxobutanoate 50 using PTC-promoted Japp-Klingemann Journal of Chemistry 7

NC CN NC CN PTC/K2CO3 PTC H CH2(CN)2 + CS2 Dioxane/TBAB EtOCH=C(CN)(X) CN 5 S SH HS S 8a, b X

NC NH NC NH2 PTC CN CN HS S S S X X 31a, b X: a = CN; b = COOEt EtOOC CN EtOOC CN PTC H PTC CN NCCH COOEt + CS EtOCH=C(CN)(X) 2 2 S S 11 SH 8a, b S X PTC OH EtOOC NC NH2 + CN CN S S S S X COOEt 32a, b X: a = CN; b = COOEt 33b

Figure 13

Me Me Me N NCS NH N −SO SO + PTC 2 2 SO2 Cl N N N S S 33 34 35

Figure 14

O O CN HOOC CN

HN BrCH(CN) NH O 2 + HN 2 N PTC N O HO O NH2 Ph Ph 36 37 38

Figure 15

O CN HOOC CN HOOC CN H O H O NH 2 2 HN 2 H N + PhNHNH2 OH− 2 OH− N O N NH HO O 2 O NH2 Ph Ph

38 37

Figure 16 8 Journal of Chemistry

CHO R PTC R + ClCH2COOR1 Microwave COOR1 OH O

39 40 41

Figure 17

CN NC-CH-CH2-CH2Cl ClCH2CH2CH2CN + Ar-CHO Ar-CH-OH O Ar 42 43 44

Figure 18 X O CH3

HO OH

K2CO3/TBAHSO4 H C O + 2X COCH Br 3 H3C 2 EDC O O O O

45

CH3 46 X

X = H, Cl, NO2, CH3, OCH3, OCH3, Br

Figure 19

R CN R CN R NH2 1 1, HSCH2COOR , HCl 2, KOH, ArCN 18-C-6, H OH 60–70∘C COOR1 H S COOR1 S

47a–f 48a–f

R R1 a, ph COOMe b, 4-O-CH3 COOMe c, benzo[b]furyl-2 COOMe d, thinyl-2 COOMe e, dimethyl 2,5-thinyl COOMe COOEt f, C6H5

Figure 20 reaction to form the ring-opened aryl hydrazones 51.These nitriles took place in high yield and low diastereoselectivity aryl hydrazones were cyclized and converted into the corre- in phase-transfer catalysis conditions (solid potassium car- sponding indole derivatives 52 by adding hydrochloric acid bonate, triethylbenzylammonium chloride (TEBA)) in aceto- in ethanol [30](Figure 21). nitrile as a solvent [31](Figure 22). Synthesis of dimethyl phosphinyl substituted tetra- When Schiff base 53 and ethyl cinnamate 56 reacted hydropyrroles 55 via 1,3-cycloaddition reaction of the azome- under different phase-transfer catalysis conditions (10 equiv- thine 53 to electron deficient alkenes such as 𝛼,𝛽-unsaturated alents of aqueous NaOH (50%)/TEBA/DMSO), the ester ketones (e.g., benzylideneacetophenone 54), esters, and of pyrrolidinecarboxylic acid 57 has not been formed; Journal of Chemistry 9

COOC2H5

O CH3 N N+ NH2 O O HCl/HNO2 NCl 50 0–5∘C R 49 R

COOC2H5 CH H O 3 COOC H N O 2 5 N O N HN N R HCl

O

52 51 R

Figure 21

Cl O P H3C N H3C H5C6 COPh 53 O + P N H3C H Ph COPh H3C Cl

54 55

Figure 22

H5C6 COOEt

O O P P C H -Cl-4 NaOH/H2O H3C N 6 4 H3C N C6H4-Cl-4 H CH3CN H3C H3C 53 57 +

Ph H C COOEt 5 6 COOH NaOH/T.E.B.A. /H2O DMSO. O 56 P N H3C C6H4-Cl-4 H H C 3 58

Figure 23

instead the acid itself 58 wasobtainedasamixtureoftwo derivative 60 was the product of a reaction of 3-methyl- diastereoisomers [31](Figure 23). 1-phenyl-2-pyrazoline-5-one 59 with CS2 and chloroac- etonitrile in equimolar ratio under solid-liquid technique 2.2. Synthesis of Five-Membered Ring Heterocycles Contain- (benzene/K2CO3/TBAB) [23](Figure 24). ing Two Heteroatoms. (4Z)-4-(4-amino-1,3-dithiol-2-ylid- Similarly, 1-phenyl-3,5-pyrazolidinedione 36 was treated ene)-5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one with CS2 and ethyl chloroacetate under the same condition 10 Journal of Chemistry

H3C CH3 S N + CS + ClCH CN PTC O N 2 2 N N S Ph

Ph H2N O 59 60

Figure 24

EtOOCH2CS S O O O S SH HN ++CS ClCH COOEt COOEt O 2 2 HN HN N O O N N Ph Ph Ph 36 O S O HN S −EtOH N Ph O 61

Figure 25

S S NH2 S N S NC N CS /ClCH CN 2 2 S P.T.C. NH2 NH 2 S COOEt NH2 NC 63 S S COOEt S 62 S N S O S CS2/ClCH2COOEt NC P.T.C. N S O S COOEt 64

Figure 26 Journal of Chemistry 11

S

NH2 S NH2 N NC NC CS /Br(CH ) Br S 2 2 2 N S P. T. C COOEt S S S S COOEt 62 65

Figure 27

Ph Ph

N N O PTC (CH2)nCH2Br N + Br(CH ) CH Br N NH 2 n 2 H3C CH3 n = 0, 1 a, n = 0, S 67a, b b, n = 1 66

Figure 28

R–CH=CH + − 2 69 X-CH2-N-NHAr [CH2=N-N]-Ar N R 68 N 70 Ar

Figure 29

N + PTC H3C SO2CH2NC RCHO H3C SO2 O

71 72 74 R

N PTC H3C SO2CH2NC + R1CH=NR2 H3C SO2

N 71 73 R2 75 R1

Figure 30

S

N H3C N H3C N Me PTC CH + N=N S CH3 N N R Me R CH3 Cl N CH3 76 77 78 CH3

Figure 31 12 Journal of Chemistry

S

NH Ph N S HN Br O + PTC N Br H

O Ph H 79 80 81

Figure 32

Y Ph Y O X Y PhHN Z N KOH Cl + S PhNCS = O Dioxan X Z Cl, OEt or NH2 X KS

82a–g 83a–g

a: X, Y = CN; b: X = CN, Y = CO2Et = = c: X, Y = CO2Et; d: X COPh, Y COCH3

e: COCH3, Y = CO2Et; f: X = COPh, Y = CO2Et

g: X, Y = COCH3

Figure 33

(benzene/K2CO3/TBAB) to give the corresponding (4Z)-4- substituted phenyl, heteroaryl, and alkyl) under liquid-liquid (4-oxo-1,3-dithiolan-2-ylidene)-1-phenylpyrazolidine-3,5- condition [35, 36](Figure 30). dione 61 [25](Figure 25). The interaction of 3-chloro-3-methyl-1-butyne 76 with The addition reaction of ethyl 3,4-diamino-5-cyanot- 4,6-dimethyl-5-arylazo-2-thiopyrimidine 77 under liq- hieno[2,3-b]thiophene-2-carboxylate 62 to carbon disul- uid-liquid phase (benzene/aq. KOH/BTEACl) afforded 4,6- fide, followed by cyclization reaction through the treat- dimethyl-5-[2-(2-methylprop-1-enyl)-1H-benzimidazol-1-yl] ment with chloroacetonitrile or ethyl chloroacetate under pyrimidinyl-(5H)-thiones 78 [37](Figure 31). PTC conditions (K2CO3, TBAB, dioxane), furnished 3,4- Reaction of 5-phenylmethylene thiohydantoin 79 with bis(4-amino-2-thioxo-1,3-thiazol-3(2H)-yl)-5-propanoylthi- 1,2-dibromoethane 80 under liquid-liquid conditions (ben- eno[2,3-b]thiophene-2-carbonitrile 63 and 3,4-bis(4-oxo-2- zene/aq. NaOH/TBAB) afforded 2,3-dihydro-6-phenylmeth- thioxo-1,3-thiazolidin-3-yl)-5-propanoylthieno[2,3-b]thio- ylene-5-oxo-imidazo[2,3-b]thiazole 81 [38](Figure 32). phene-2-carbonitrile 64, in satisfactory yields [32](Figure A variety of 4-thiazolidinone derivatives 83a–g were suc- 26). cessfully synthesized via in situ formation of ketene- Moreover, the addition reaction of compound 62 to N,S-acetals 82a–g whichinturnwasreactedwithethyl carbon disulfide followed by cycloalkylation reaction with chloroethyl acetate, chloroacetamide, or chloroacetyl chlo- 1,2-dibromoethane, at 1 : 1 : 1 molar ratio under same PTC ride followed by ring closure to afford the desired 4- conditions, afforded the corresponding bis-1,3-dithiolan-2- thiazolidinones 83a–g [39](Figure 33). ylidene 65 [32](Figure 27). Treatment of triazepene compound 66 with dibromides One of the medicinal applications for PTC techniques is using liquid-liquid condition (benzene/NaOH/TBAB) fur- synthesis of sibenadet hydrochloride 87 which is a potent nished pyrazole derivatives 67a, b [33](Figure 28). drug used for treatment of chronic obstructive pulmonary 1,3-Dipolar cycloaddition of various substituted nitril- disease. This bioactive molecule was synthesized by O- imines 68 to the appropriate alkenyl dipolarophiles 69 in alkylation of phenylethanol 84 with the alkyl bromide 85 aqueousmediaandinpresenceofasurfactantaffordeda under PTC condition to form the alkylated product 86 in number of 1-aryl-5-substituted-4,5-dihydropyrazoles 70 [34] 97% yield. Reaction of 86 with benzothiazole derivative led (Figure 29). to formation of the desired product 86 [40](Figure 34). Preparation of 5-substituted oxazoles 74 or imidazoles Treatment of an equimolar amount of 2-mercapto- 75 was achieved by reaction of p-tolylsulphonylmethyl iso- quinazolin-4(3H)-one 88 and dihalocompounds such as 1,2- cyanide 71 with aldehydes 72 R1CH=NR2 or 73 (R1,R2 = dibromoethane and chloroacetyl chloride underwent S- and Journal of Chemistry 13

OH O CH2 NaOH/H2O + H2C TBAHSO4 Br

84 85 97% 86

OH O S O NH O NH ·HCl S

Sibenadet hydrochloride 87 O

Figure 34

O

N Br(CH2)2Br

N S O H 89 NH P.T.C. O O N SH H N ClCH2COCl S N H 88 90

Figure 35

Ph

O N S

N H CS2/ Br(CH2)2Br S P.T.C. S

Ph 92a O N S

N Ph H N 91 O S N CS2/Br(CH2)3Br H P.T.C. S S

92b

Figure 36 14 Journal of Chemistry

O NH Ph H3C NH H3C N N BrCH2COOEt/P.T.C. X R T.B.A.B. H3C N O N N H3C X N O Ph Ph 93 X = S 95a, b = 94 X O X, a = S b = O

Figure 37

NHPh

N H N H Br Ph N N HN PTC + N Ph O N Br H Ph H O

96 97

OH O N N H N O NH Br PTC N ++N N O HN Br HN O O

Ph Ph H Ph 98 99a 99b

Figure 38

N CH CH 3 N 3 N

CH3Cl, 50% NaOH aq NC CN NC CN T.E.B.A. NC CN H C CH3 3 CH H C 3 3 CH H3C 3 100 CH3 H3C 101 Anastrozole

Figure 39

+ N N N N S PTC R(Ar) N N + + R(Ar)S N N 104 102 103

Figure 40 Journal of Chemistry 15

R

R N N N Cl N N

Bu4NBr/CHCl3-H2O R + NaN N N 3 N N Cl N N N N Cl N N R

R R 105 106a–e

R = OMe (a), OEt (b), Me (c), H (d), Br (e)

Figure 41

NH2 H2N

NC CN PTC + CS + XCH Y Y 2 2 Y S S 5 X = Cl, Br 107a, b

a,Y = COOEt b, Y = CN

Figure 42

H3C CH3

H3COC COCH3 + CS2 + ClCH2CO2C2H5

C2H5O2C CO2C2H5 SS 108 109

Figure 43

H2N NH2

CH (CN) + PhNCS + ClCH CO Et 2 2 2 2 CO Et EtO2C 2 57 SN Ph 110

Figure 44

CH S 3 S CH3 CH S 3 N N + CS2 + ClCH2CN NC S O N N N O Ph N NC Ph 63 Ph 111

Figure 45 16 Journal of Chemistry

O S S O O S −H2O S + CS + ClCH R R HN HN 2 2 O N HN N O N Ph Ph R 36 Ph 112 R = CN, COOEt

Figure 46

S S S S Br PTC + CH3

114 OH 113 115 O

Figure 47

N-cyclo-alkylation by using PTC conditions, giving 2,3-di- alkyl(aryl)thiocyanates 102 with azide 103 under PTC con- hydro-5H-[1,3]thiazolo[2,3-b]quinazolin-5-one 89 and 5H- ditions [44](Figure 40). [1,3]-thiazolo-[2,3-b]quinazoline-3,5(2H)-dione 90,respec- Functionally substituted tetrazoles have been synthe- 󸀠 󸀠󸀠 tively [41](Figure 35). sized from the corresponding N,N ,N -triarylbenzene-1,3,5- The PTC reaction of 3-phenyl-2-thiohydantoin 91 with tricarboxamides 105 via sequential transformation of these dihalocompounds, namely, ethylene dibromide or 1,3-dibro- compounds into imidoyl chlorides and treatment of the mopropane, with CS2, yielded 1,3-dithioxane derivative 92a latter with sodium azide under conditions of phase-transfer or 5-(1,3-dithian-2-ylidene)-3-phenyl-2-thioxoimidazolidin- catalysis. As a result, a number of heterocyclic structures 4-one derivative 92b,respectively[42](Figure 36). 106a–106e containing three tetrazole rings have been isolated Treatment of the thiourea 93 and urea 94 derivatives [45](Figure 41). with ethyl bromoacetate under PTC condition using TBAB as a catalyst and benzene/anhydrous K2CO3 as liquid-solid phases gave imidazolidinediones 95a, b via ring closure pathway [43](Figure 37). 3. Synthesis of Fused Five-Membered Ring Heterocycles 2.3. Synthesis of Five-Membered Ring Heterocycles Containing Functionally substituted thieno(2,3-b)thiophenes 107a, b Three Heteroatoms. Alkylation of (2Z,5Z)-5-benzylidene- were synthesized in a one-pot reaction of malononitrile 5, 2-(hydroxyimino)imidazolidin-4-one 96 with methylene CS2,and𝛼-halocarbethoxy or 𝛼-halonitrile electrophiles in bromide in benzene/aq. NaOH in presence of TBAB as a 1 : 1 : 2 molar ratios using (benzene/K2CO3/TBAB) as a PTC catalyst gave 2-phenyl-2,3-dihydro-6-phenylmethylene-5- condition [23](Figure 42). oxo-imidazo[2,1-c]-1,2,4-triazole 97. On the other hand, Another different thienothiophene 109 was synthesized alkylation of the oxime derivative of 5-phenylmethylene via the reaction of acetylacetone 108 with CS2 and ethyl thiohydantoin 98 with methylene bromide gave 3-(1H)-6- chloroacetate in 1 : 1 : 2 molar ratio under the same experi- phenylmethylene-5-oxo-imidazo[2,1-c]-1,2,4-oxadiazoles mental conditions [46](Figure 43). 99a, b [38](Figure 38). Thieno(2,3-b)pyrrole derivative 110 was obtained by Anastrozole 101 which acts as selective aromatase inhib- treating malononitrile 5 with phenyl isothiocyante 7 and itor and is employed effectively in treatment of advanced ethyl chloroacetate in 1:1:2 molar ratio using (benzene/ breast cancer in postmenopausal women has been syn- K2CO3/TBAB) as a phase transfer catalyst [23](Figure 44). thesized in good yield by methylation reaction of 3,5- Likewise,underthesameconditions,3-methyl-1-phenyl- bis(cyanomethyl)toluene 100,usingmethylchlorideand50% 2-pyrazoline-5-one 63 was subjected to react with CS2 and aq. NaOH/TEBA as a PTC condition [40](Figure 39). chloroacetonitrile in 1 : 1 : 1 molar ratio where 6-cyano-4,6- dihydro-3-methyl-1-phenylthieno(3,4-c)pyrazol-4-thione 111 2.4. Synthesis of Five-Membered Ring Heterocycles Con- was obtained in good yield [23](Figure 45). taining Four Heteroatoms. 5-Alkyl and 5-arylthiotetrazoles 1-Phenyl-3,5-pyrazolinedione 36 was allowed to react 104 were synthesized in good yield from reaction of with CS2 along with chloroacetonitrile or ethyl chloroacetate Journal of Chemistry 17

O Ar O N Ph O O N N N Ph

117 O Ar O Ar O X X Ar O CO or CO CH 2 2 3 N CH N N N 3 N + PTC X X H N H Or Br− H X = CO2CH3 CO2CH3 H H3CO2C 118a 118b 116 Ar O

H N N Z H Z Z = CN, CO2C2H5 H 119 Ar O

H(CO C H ) X Y N N 2 2 5

X = H, CO2C2H5 Y = CO2C2H5, CO2CH3 CO2CH2H5 120

Figure 48

NH NH 2 2 NH2 NH2 H2N NH2 NC CN + 2XCH Y PTC 2 Y Y S HS N N SH S NN X = Cl, Br 121 122

Y = COOEt, CN, PhCO, CONH2 NH2 NH2 NC CN

PTC + 2HSCH2COOEt Cl N N Cl

123

Figure 49 under the same conditions to give the corresponding thioxo- cycloadduct products 117–120 with high stereospecificity in thienopyrazolone derivatives 112 [25](Figure 46). the presence of KF and trioctylmethylammonium chloride Reaction of 4-hydroxydithiocoumarin 113 with allyl or without solvent in the presence of aliquat 336 as phase bromide 114 under liquid-liquid technique (CH2Cl2/aq. transfer catalyst [48](Figure 48). NaOH/TBAB or TBACl) gave 2-methyl-2,3-dihydro-4H- Under solid-liquid technique (dioxan/K2CO3/TBAB), thieno[2,3-b]benzothiopyran-4-one 115 [47](Figure 47). bis-thieno(1,8)naphthyridines 122 were prepared by reac- Treating of pyridazinium ylides 116 with N-phenyl- tion of 4,5-diamino-3,6-dicyano-(1,8)naphthyridine-2,7- maleimide, maleic and fumaric esters, resulted in the dithiol 121 with ethyl chloroacetate, chloroacetonitrile, 18 Journal of Chemistry

NH2 NH2 PTC NC 1 : 1 Y N S H3CS NH2 125 NC CN

+ XCH2Y N H3CS SH X = Cl, Br Y 124 NH NH2 H2N PTC 1 : 2 Y S N H3CS 126

Y = COOEt, CN, PhCO, CONH2

Figure 50

R NH2 H CH NH N 2 2 N PTC + XCH2R Z Y Z Y

Z = CN, CO C H 129, 130 127, 128 2 2 5 Y = S, O X = Cl, Br

R = CN, CO2C2H5, COPh R NH2 H N CH2NH2 PTC N + XCH2R N Z N Y H Y = NH2, OH X=Cl, Br R 132 R = CN, CO2C2H5, COPh Z = CN, CO2C2H5 131a, b

Figure 51

phenacyl bromide, or chloroacetamide in 1 : 2 molar ratio which afforded the corresponding substituted pyr-rolo[2,1- or from reaction of 4,5-diamino-2,7-dichloro-3,6-dicy- b]benzothiazoles 129 or substituted pyrrolo[2,1-b]ben- ano(1,8)naphthyridine 123 with two equivalents of ethyl zoxazoles 130,respectively[42]. Similarly, (3-amino-2-(1,3- mercaptoacetate [49](Figure 49). dihydro-2H-benzimidazol-2-ylidene)propanenitrile malo- Similarly 4-amino-3,5-dicyano-2-mercapto-6-methylthi- nonitrile 131a or ethyl 3-amino-2-(1,3-dihydro-2H-benzim- opyridine 124 was reacted with ethyl chloroacetate, chloro- idazol-2-ylidene)propanoate 131b were treated under the acetonitrile, phenacyl bromide, or chloroacetamide in 1 : 1 same PTC conditions, where the corresponding pyrrolo[2,3- molar ratio using the same PTC condition to give the cor- b]pyrrolo[1,2-f]benzoimidazoles 132 were obtained [50] responding thieno(2,3-b)pyridines 125 or pyrrolo(2,3-d) (Figure 51). thieno(2,3-b)pyridines 126 [49](Figure 50). Reaction of 2,7-dichloro-1,8-naphthyridine derivative 133 Using solid-liquid technique (dioxan/K2CO3/TBAB), 2-ylidenemalononitrile and ethyl 2-ylidenecyanoacetate of with ethyl glycinate hydrochloride in 1 : 1 molar ratio under both 2,3-dihydrobenzothiazole 127 and 2,3-dihydrobenzox- solid-liquid technique (dioxan/K2CO3/TBAB) afforded the azole 128 were allowed to react with chloroacetonitrile, corresponding bis-pyrrolo(1,8)naphthyridine derivative 134 ethylchloroacetate,orphenacylbromideinequimolarratio [49](Figure 52). Journal of Chemistry 19

NH2 NH2 NH2 NH2 H2N NH2 NC CN PTC EtOOC COOEt + HCl.H2NCH2COOEt Cl N N N N N N Cl H H 133 134

Figure 52 Ph(p-Cl) Y PTC CN Ph(p-Cl) 1 : 1 C2H5O2C Z S S NH 136 + ClCH2CO2C2H5 HS S NH C2H5O2C N S S CO C H Z = CN, CHO, PhCO PTC 2 2 5 135 1 : 2 H2N Y Ph(p-Cl) 137 Y = NH2, H, Ph

Figure 53 Ph NN ClCH2CN NC (1 : 1: 1)/PTC NH2 S S 139 Ph NN ClCH2CO2Et C2H5O2C (1 : 1: 1)/PTC NH2 S S 140 Ph Ph NN N NH PhCOCH2Br + PhOC COPh (1 : 1: 1)/PTC NH2 HO S S S S Ph 141 142 N N CS2 Ph Ph PTC NN N ClCH2CO2Et N O NH2 NH 138 (1 : 1: 2)/PTC EtO2C NH2 O + EtO2C S S S SCH2COPh 143 144 Ph Ph NN NN PhCOCH2Br PhOC + PhOC N (1 : 1: 2)/PTC NH2 S S Ph S SCH2COPh 145 146 Ph N N ClCH2CN N NH2 (1 : 1: 2)/PTC NC S S 147

Figure 54 20 Journal of Chemistry

NC S NH2 NH2

PTC + PhCOCH Br COPh CN 2 S S S N H COOEt EtOOC 31b CN 148

Figure 55

NH Y 2 NH2 X

PTC PhOC CN CN + PhCOCH2Br S N HS N CN Ph Ph CN 149a, b 150a, b

a; X = CN, b; X = COOEt a; Y = NH2 b; Y = OH

Figure 56

O O OH R O O O O

+ PhCOCH2Br

CH3 O CH3

151 152 R

− R = 4-ClC6H4, 4-MeOC6H4

Figure 57

O O HO OH O O

+ PhCOCH2Br R R

p 154 O O R R 153 R =p-Cl-C6H4, p-MeOC 6H4

Figure 58

HO OH O O O O + PhCOCH Br R 2 R

O O R R 156 155 R =p-Cl-C6H4− , p–MeOC6H4−

Figure 59 Journal of Chemistry 21

HO OH X COCH2Br Ar O O Ar + (Ar)R R(Ar) O O O O (Ar)R R(Ar) 157 158

Figure 60

H C CN 3 H3C

PTC NH2 N + BrCH(CN)2 O N N N O

Ph Ph 63 159

Figure 61

Thieno(2,3-b) thiopyran derivatives 136 were obtained Treatment of 3-methyl-1-phenyl-2-pyrazolin-5-one 63 from reaction of the thiopyran derivative 135 with ethyl with bromomalononitrile in 1 : 1 molar ratio yielded 5- chloroacetate in 1 : 1 molar ratio (dioxan/K2CO3/TBAB), amino-4-cyano-3-methyl-1-phenylfuro(2,3-c)pyrazoline 159 whileoncarryingoutthesamereactionunderthesame [23](Figure 61). conditions but in 1 : 2 molar ratio gave the corresponding Furo(1,5)benzodiazepin derivative 161 was obtained thienopyrrolothiopyran derivatives 137 [51](Figure 53). by reaction of 1,4-dimethyl-3H-(1,5)benzodiazepin-2-one Treatment of 3-amino-1-phenyl-2-pyrazoline-5-one 138 160 with chloroacetonitrile under solid-liquid condition with CS2 along with chloroacetonitrile, ethyl chloroacetate, (dioxan/K2CO3/TBAB) [57](Figure 62). orphenacylbromidein1:1:1 and1:1:2 molarratiosusing By reaction of 4-methyl-1,3-dihydro-2H-1-benzazepin- [dioxan/K2CO3/TBAB] as a PTC gave the corresponding 2-one 162 with chloroacetonitrile or phenacyl bromide thienopyrazoles 139–143, 145 and respectively, 144, 146 and under the solid-liquid phase transfer catalyst (dioxan/ 147,fusedthiazines[52](Figure 54). K2CO3/TBAB), the corresponding pyrrolo[1,2-a](1,5)benzo- Thieno(3,4-b)pyrrole derivative 148 was obtained by diazepine 163 was obtained [58](Figure 63). reacting ethyl thiophene-2-ylidenecyanoacetate derivative Synthesis of 2,6-di(1-acetyl-2-oxopropylidene)dithiolo 󸀠 󸀠 31b with phenacyl bromide in a heterogeneous mixture of [4,5-b:4 ,5 -e]-4,8-benzoquinone 166 was achieved in (dioxan/K2CO3/TBAB) as a PTC [19](Figure 55). one-pot reaction under solid-liquid technique (benzene/ In the same manner, pyridin-2-ylidenemalononitriles K2CO3/TBAB) starting from acetylacetone, CS2 to give 165 149a, b were reacted with phenacyl bromide under the same whichinturnreactedwithtetrabromop-benzo-quinone 164 reaction condition and yielded the corresponding thieno(2,3- in 2 : 1 molar ratio [59](Figure 64). b)pyridine derivatives 150a, b [18](Figure 56). Treatment of 4-arylidene-1-phenyl-3,5-pyrazolinediones 2,6-Dibenzoyl-5-methyl-3-(substituted styryl)benzo[1,2- 167 with S,S-acetal derivatives using solid-liquid tech- b:5,4-b]difurans 152 were synthesized from reaction of cin- nique (dioxan/K2CO3/TBAB) yielded the corresponding namoylbenzofurans 151 with phenacyl bromide under liq- pyrazolino-(1,3)-dithiolane derivatives 168 [25](Figure 65). uid-liquid technique (benzene/aq. K2CO3/TBAHSO4)[53] Some condensed heterocyclic systems 171 were obtained (Figure 57). by reacting 3-phenyl-4-amino-s-triazole-5-thiol 169 as a 󸀠 Similarly, 2,6-dibenzoyl-3,5-distyrylbenzo(1,2-b:5,4 -b) dianionic compound containing N and S poles with some difurans 154 were prepared by condensing substituted dichal- di- and tetrahaloderivatives 170 as well as 𝛼-haloketones and cones 153 with phenacyl bromide under the same preceding 𝛼-halonitrile derivatives under solid-liquid technique [60] PTC conditions [54](Figure 58). (Figure 66). Also, under the same PTC conditions, dibenzoylbenzod- 2-Aminoprop-1-ene-1,1,3-tricarbonitrile 172 was reacted ifurans 156 were obtained from the reaction of substituted with CS2 or PhNCS along with 3-methyl-1-phenyl-2-pyr- resorcinols 155 with phenacyl bromide [55](Figure 59). azoline-5-one 63 or 2-iminothiazolidin-4-one 173 (dioxan/ Moreover, 2,6-diaroyl/naphthoyl-3,5-dialkyl/phenylben- 2 3 174 󸀠 K CO /TBAB) to give the corresponding fused pyrazoles zo[1,2-b:5,4-b ]difurans 158 were synthesized by condensing and thiazoles 175,respectively[61](Figure 67). 2,4-diacyl/diaroylresorcinols 157 with various p-substituted The reaction of 1,3-dihydro-4-methyl(1,5)benzodiazepin- 𝛼 -bromo ketones [56](Figure 60). 2-one 176 with chloroacetonitrile using solid-liquid 22 Journal of Chemistry

H3C H C O 3 O NH2 N N

+ ClCH2CN

N N CH3 CH3 160 161

Figure 62

NH2

O O NH N PTC + ClCH CN 2 Dioxan N N CH3 CH 162 163 3

Figure 63

O O

Br Br H3COC S S COCH3 KS COCH 3 PTC + H COC S S COCH KS COCH 3 3 Br Br 3 O O 165 166 164

Figure 64

Ar Ar O Ar S X O O S PTC CN −H2O HN + CS2 + XCH2CN S X HN HN N O O S N N Ph Ph CN Ph 168 167 X = CN, CO2Et X = CN, COOEt Ar = p-ClC6H4, p-NO2C6H4

Figure 65

Ph O O H N N Br Br N S N PTC N SH N N Ph N + N N Br Br N S NH2 H Ph O 169 O 170 171

Figure 66 Journal of Chemistry 23

CH 3 Ph N N N NH N 2 Ph CN H3C O 63

X S N NH2 H N CN 2 174 + X= C= S O NC HN CN NH 172 NH NH2 S NH X = S, NPh S 173 CN

X N S NH2 175

Figure 67

NH2

O H O N N PTC + ClCH2CN

N N CH3 CH3 167 177

Figure 68

Me Me

− − PTC O + (Ph3PCH2–CH=CH–CH3)Cl N O O O 179 O MeON 180 O

178 H3C

Figure 69

Ph Ph

N N + BrCH CH Br S 2 2 S N N H C H3C NH 3 N

S S 182 181

Figure 70 24 Journal of Chemistry

NH2 Ph O N H XH N S S X

184 X = O, S, NH

YH Ph O Ph O N Y N PTC ZH S S Z S S Br 185 Br 183 Y = Z = NH, O Ph O HSCH CH XH 2 2 N S

S S X 186 X = NH, O

Ph O H NNHCSNH N 2 2 S NH2 S S HN N 187

Figure 71

technique (dioxan/K2CO3/TBAB) gave the corresponding yielded the corresponding spiro-1,3-dithiolane derivatives oxazolo-(1,5)benzodiazepin derivative 177 [57](Figure 68). 189 [25](Figure 72). When 7-(methoxyimino)-4-methyl-2H-chromene-2,8- 1-Benzoyl-3,3-dibromo-4-phenyl-(1,5)benzodiazepin- (7H)-dione 178 was treated with crotyltriphenylphospho- 2-one 190 was reacted with different dinucleophiles under nium chloride (CTPPCl) 179 (CH2Cl2/Li(OH)/CTPPCl), the PTC condition (dioxan/K2CO3/TBAB) to furnish the corre- corresponding chromeno-oxazolone 180 was obtained in sponding spiroheterocycles attached to benzodiazepine moi- which one of the reactants (CTPPCl) acts also as a catalyst ety 191–193 [64](Figure 73). [62](Figure 69). The triazepine 181 was treated with 1,2-dibromoethane 5. Uses of Phase Transfer Catalysis Techniques under liquid-liquid technique (benzene/aq. NaOH/BTEACl) in Reactions of Five-Membered Heterocycles to afford the corresponding 6-methyl-8-phenyl-2,3-dihy- dro[1,3]thiazolo[3,2-d][1,2,4]triazepine-5(6H)-thione 182 5.1. Alkylation and Acylation [33](Figure 70). 5.1.1. N-Alkylation or Acylation. Diez-Barra et al. [65]studied the alkylation of pyrrole 194 by PTC technique in absence 4. Synthesis of Spiro Five-Membered of the solvent. The study revealed that the N versus C ratio Ring Heterocycles is not affected by the nature of the catalyst. The nature of the leaving groups have a significant influence where N- Synthesis of spirorhodanine heterocycles 184–187 was alkylation increases in the sequence I < Br < Cl < OTs achieved by treating 5,5-dibromo-3-phenyl-2-thioxo-1,3-thi- (Figure 74). azolidin-4-one 183 with different bidentates or with mixture N-alkyl pyrroliden-2,5-diones 200 [66, 67]weresyn- of CS2 and some active methylene compounds under solid- thesized via reaction of pyrroliden-2,5-diones with different liquid condition (dioxan/K2CO3/TBAB) [63](Figure 71). alkylating reagents under phase transfer catalysis condition Reaction of 4-ethoxymethylene-1-phenyl-3,5-pyrazoli- (toluene/K2CO3/TBAHSO4) according to (Figure 75). dinedione 188 with CS2 and malononitrile 5 or ethyl cyanoac- N-allylindoles 203 were easily carried out via N-allylation etate 11 using solid-liquid technique (dioxan/K2CO3/TBAB) of the proper indoles 201 with the suitable allyl halides 202. Journal of Chemistry 25

S CN O OEt O

PTC S X + CS + NCCH X HN 2 2 HN O O N 5 or 11 N Ph Ph 189 188 X = CN, COOEt

Figure 72

XH COPh O YH N X

Y N 191 Ph X = NH, S Y = O, S, NH

XH COPh COPh O O N N X Br YH Y Br N N 192 Ph 190 Ph X = NH, S Y = O, S, NH

COPh O NH N S 2 H2NNHCSNH2 N N N H 193 Ph

Figure 73

R

RX PTC + N + N N R N H H H R

161 162 163 164

Figure 74

O O

NH + XCH2CH= CHCH2OR N CH2CH= CHCH2OR

O O 198 199 200

Figure 75 26 Journal of Chemistry

󳰀󳰀 R󳰀󳰀 R X

+ CH2 R N 󳰀󳰀󳰀 N 󳰀 󳰀󳰀󳰀 CH R H R R 2

201 203 202 R 󳰀 󳰀 󳰀󳰀 R R, R = H, CH3; R = H, CH3, CH2CH2OCH3, CHO, CH2COOCH3; 󳰀󳰀󳰀 R = H, 5-CH3, 7-CH3, X =

Figure 76

Cl O O N + R3 N R1 H R R1 3 R2

204 205a, b R2 206a–c

a; R1 = H, R2 = CH3

b , c; R1 = CH3, R2 = CH3, R3 = H

Figure 77

R (CH )Cl R 2 2 THF, NaNH2 R N N H Bu4NHSO4 CH3PPh3Br N O aq.NaOH O R = H

Cl 204 207 208

(a) R = H (b) R = CH3

Figure 78

The reaction was accomplished in diethyl ether via a phase via its reaction with sodamide using solid-liquid technique transfer process in which 18-crown-6 was employed as the (THF/NaNH2/CH3Ph3Br) [70](Figure 78). transfer agent and t-BuOK as the base [68](Figure 76). Synthesis of a series of N-alkylpyrrolidino[59]fullerenes 2-Substituted 1-allylpyrroles 206a–c were easily prepared was achieved via the combination of PTC without sol- from reaction of 2-formylpyrrole or 2-acetylpyrrole 204 with vent and microwave irradiation technique. Thus, 2-phe- either 3-chlorobut-1-ene 205a or 3-chloro-2-methylprop- nylpyrrolidinofullerene 209 was treated with benzyl, p-ni- 1-ene 205b, respectively, under phase transfer conditions trobenzyl, p-methyloxy-carbonylbenzyl, n-octyl, or allyl bro- (toluene/NaOH/TBAHSO4)[69](Figure 77). mides in microwave oven in presence of K2CO3 and TBAB Treatment of pyrroles 204 with 1,2-dichloroethane in to yield the corresponding N-alkylpyrrolidino[59]fullerenes presence of 50% NaOH and TBAB as a catalyst yielded 210 [71](Figure 79). the corresponding N-chloroethyl-pyroles 207 in excellent 1,3-Bis[2-(aryl)indol-1-yl]propanes 213 and 1,3-bis[3- yield which was transformed into 1,2-divinylpyrroles 208 (aryl)-5-(aryl)pyrazol-1-yl]-propanes 214 were prepared Journal of Chemistry 27

Ph Ph

R-Br NH PTC/MW. N-R∙

209 210

Figure 79

Ar Ar Ar Ar N NH + Br(CH2)3Br + HN N

211 213 Ar

Ar Br N 󳰀 N Ar 󳰀 2 + Ar N 󳰀 (CH2)3 N Ar N H Br N Ar 212 214

Figure 80

CN CN CN Dimethyl carbonate K2CO3, TBAB DMF, 126∘C, 26 h N N N H H H

215 216a 216b

Figure 81

from reaction of appropriate 2-arylindoles 211 and 4,5-dihy- 1-alkylated derivatives 219 and 220,respectively[74] dropyrazoles 212, respectively, with 1,3-dibromopropane, via (Figure 82). liquid-liquid technique using TBAHS as a catalyst, benzene Barraja et al. heated 2-substituted-3-bromoindoles 221 as the organic phase, and 50% KOH as an aq. phase [72] with excess of different nucleophiles, solid KOH, and (Figure 80). dibenzo-18-crown as a phase transfer catalyst to afford the Indole-2-acetonitrile 215 was treated with (CH3)2CO3 in corresponding 3-substituted indoles 222 in a satisfactory a mixture of [DMF/TBAB/K2CO3] to afford 1-methylindole- increase of yield [75](Figure 83). 2-acetonitrile 216a and 2-(1-methylindole-3-yl)propionitrile Carbazole 223 was alkylated with 1,6-dibromohexane in 216b [73](Figure 81). 1 : 1 molar ratio to give N-alkyl derivative 224 in a mixture of Alkylation of indole 217, 2,3-dimethylindole 218 with (benzene/NaOH/TBAB) [76](Figure 84). chlorodifluromethane under liquid-liquid technique Alkylation of pyrazole 225 with cyclopentyl or cyclo- (CH2Cl2/aq. NaOH/BzTEACl) afforded the corresponding hexyl bromides without solvent with PTC system (KOH/ 28 Journal of Chemistry

+ N ClCHF2 H N

CHF2 217 219

CH3 CH3

+ ClCHF2 N CH3 H N CH3

CHF2

218 220

Figure 82

Br Nu

+ NuH R R1 1 N N 221R 222 R

R = H·CH3; R1 = Ph, 2-NO2C6H5, 2-NH2C6H5, CO2Et Nu = SAr, O-Ar, NR(Ar, cylic).

Figure 83

+ Br(CH2)6Br N N H (CH ) Br 223 2 6 224

Figure 84

TBAB) afforded the corresponding 1-cyclopentyl or 1-cyclo- N-Substituted-3,5-diarylpyrazolines 237 and 238 were hexylpyrazoles 226a, b, respectively. Likewise treatment of prepared via liquid-liquid system in (CHCl3 or benzene/aq. pyrazole with 1,2-dibromoethane in 1 : 1 or 2 : 1 molar ratio KOH/TBAB) using alkyl and allyl halides, respectively, as afforded 1-bromoethylpyrazole or 1,2 bispyrazolylethane 227, alkylating agents for pyrazoles 236 [79](Figure 87). 228 [76](Figure 85). Also, alkylation reaction of 1H-pyrazole N-Alkylation reactions of 4,9-dihydro-9-methyl-4,10,10- 225 with linear or branched alkyl halide in liquid-liquid PTC trioxo-1(2H)-pyrazolo[3,4-c][2,1]-benzothiazepine 239 with system gave 1-alkyl-1H-pyrazole 229 [77](Figure 85). dimethyl sulphate, diethyl sulphate, benzyl bromide, benzyl chloride, phenacyl bromide, phenacyl chloride, or cyclo- The reaction of 3-tert-butylpyrazole 230 with dibromo- hexyl bromide under the liquid-liquid PTC condition of methane afforded bis(tert-butylpyrazol-1-yl)methane [CH2(3- (toluene/NaOH(25%)/BTEACl, TBAB, or TBAHSO4)pro- t-BuPz)2] 231.However,thereactionof3-isopropylpyra- duced1-and2-alkylatedisomers240a, b. The ratios between zole 232 with dibromomethane under the same con- these two isomers were calculated [80](Figure 88). dition yielded three isomers, namely, bis(5-isopropylpyra- A number of 4-substituted pyrazolo[3,4-d]pyrimidines zol-1-yl)methane[CH2(5-isoPrPz)2] 233,(3-isopropylpyra- 󸀠 󸀠 󸀠 241 have been reacted with (2-acetoxyethoxy)methyl bro- zol-1-yl-5 -isopropylpyrazol-1 -yl)methane[CH2(3-iPrPz- 5 - mide using liquid-liquid and solid-liquid techniques. The isoPrPz)2] 234, and bis(3-isopropylpyrazol-1-yl) methane influences of the solvent and catalyst have been studied [81, [CH2(3-iPrPz)2] 235 [78](Figure 86). 82](Figure 89). Journal of Chemistry 29

N N + N () Br () n N n H 225 226a, b n = 2, 3 1 : 1 N N

+ BrCH CH Br 227 N 2 2 CH2CH2Br N H 2 : 1 226 N N

CH2CH2 N 228 N

N + RX N N N H R 225 229

R = linear or branched alkyl C1–C6 Figure 85

t But Bu But

+ CH Br N 2 2 N CH2 N N H N N 231 230

i-Pr i-Pr i-Pr i-Pr i-Pr N + CH Br CH N 2 2 N 2 N + N CH2 N N H N N N 232 233 234

i-Pr i-Pr N N

+ N CH2 N

235

Figure 86

Imidazole 243 was alkylated with different alkyl halides 1-Alkyl-2-methyl-2-imidazolines 247 were obtained in under solid-liquid PTC in absence of solvent where the good to excellent yields by alkylation of 2-methyl-2-imid- N-alkyl imidazoles 244a and imidazolium salts 244b were azoline 246 with organic halides in the absence of solvent [85] obtained [83](Figure 90). (Figure 92). 1-Alkyl(C4–C14)imidazoles 245 were obtained from the Using the PTC condition such as (CH2Cl2/KOH/TEBA), alkylation of imidazole 243 with the appropriate n-bro- a mixture (1 : 1) of N-alkylated 5-nitroimidazoles 250a, b or moalkane via PTC technique (benzene/KOH/TBAI) [84] 6-nitrobenzimidazoles 251a, b was obtained by the reaction (Figure 91). of 5-nitroimidazoles 248 or 6-nitrobenzimidazoles 249 with 30 Journal of Chemistry

Ar Ar

N R + RX N N Ar N H Ar

236 237

Ar Ar

+ CH2 = CH-CH2-X N N N Ar H N Ar 236 238

Figure 87

O O O O R O R CH 3 S N S N O R S N RX or R2SO4 N + N N N N H R N O O O (1H-isomer) (2H-isomer) 239 240a 240b

Figure 88

R R

N N NH + CH3CO2CH2CH2OCH2Br N CH2O(CH2)2CO2CH3 N N N N 241 242

Figure 89

R + N N N + RX + N N N H H R 243 244a 244b RX = EtI, n–BuCl, BnCl

Figure 90 Journal of Chemistry 31

N N + RBr N N H 243 R

245 R = CH3(CH2)n, n=3–13

Figure 91

H H N N PTC CH CH3 + RX 3 N N R 246H 247

Figure 92

CH3 N O N N N O2N 2 O2N + CH3I + N N N CH H 3 250b 248 250a

CH2Ph O2N O2N N O2N N N + + PhCH2Cl N N N H CH2Ph 249 251a 251b

Figure 93

R 1 R

NH (CH2)nCH3 N TEAI, NaOH, C6H5CH3 NN + CH3(CH2)nCH2Br Or, TBAB, Na2CO3, CH3CN R 2 R 252a, b 253 254

a, R1 = CH3, R2 = H b, R1 = CH3, R2 = NO2

Figure 94

R H N O N O K CO /TEBACl + RX 2 3 CH CN N CH 3 3 N CH3

256 257

Figure 95 32 Journal of Chemistry

N N PTC Ph + ClCHF2 Ph N H

CHF2 258 259

Figure 96

R R

NNH TBAB, K2CO3, CH3CN NN(CH2)nCH3 + CH3(CH2)nBr

260 261 262

Figure 97

Ph H C H3C 3 H3C O O O + PhCH2Cl + H3C H3C ON O N H3C H ON Ph 263 264a 264b

Figure 98

R H NN NN + RX N N 265 266

N N N + RX N N N H R 267 268

N N N N − + ArX N + N Ar N N H N Ar−

267 269a 269b

Figure 99 Journal of Chemistry 33

N N N + ClCHF2 N N H N CHF2 267 270

Figure 100

CH3 CH3 CH CH3 3

K CO , KOH, CH CN + RBr 2 3 3 N N N N Bu4NBr + + N N N N N R N R H N 272 R 271 R = alkyl, benzyl, ... 273a 273b 273c

Figure 101

Ph Ph H Ph CHF2 N N N + ClCHF N N N 2 N N N + N N N CHF2

274 275a 275b

Figure 102

methyl iodide or benzyl chloride, respectively, in a satisfac- 261 under PTC condition (TBAB/K2CO3/CH3CN) [89] tory yield [86](Figure 93). (Figure 97). Different imidazole compounds such as 2-methylim- Competitive N versus O benzylation of 5,5-dimethyl- idazole 252a and 2-methyl-4-nitro imidazole 252b were 3-isoxazolidinone 263 using (CH2Cl2/NaOH) using dif- reacted with different alkyl bromides 253 in an alkaline ferent PTC catalysts was studied. The ratio of N-/O- media, at reflux temperature and in the presence of tetraethy- alkylations 264a/264b was2/3formostcasesofcatalysts[90] lammonium iodide (TEAI) or TBAB as PTC and afforded 1- (Figure 98). alkyl imidazole derivatives 254 which exhibited a variety of Alkylation of 1,2,4-triazole 265 and benzotriazole 267 valuable pharmacological properties [87](Figure 94). has been performed either in basic media under solvent N-Alkyl-2-acetylbenzimidazoles 257 have been obtained free PTC conditions or in absence of base by conventional in over 90% yield by alkylating 2-acetylbenzimidazole 256 and microwave heating. Several parameters affecting the using the PTC mixture of (CH3CN/K2CO3/TEBACl) at room selectivity have been studied [91]. Arylation of 1H-1,2,3- temperature [88](Figure 95). benzotriazole 267 with activated aryl halides in a medium of 2-Phenylbenzimidazole 258 was alkylated with chlorod- aromatic hydrocarbons under PTC condition using inorganic ifluromethane under liquid-liquid condition (CH2Cl2/aq. bases and acetyltrimethylammonium bromide as a phase NaOH/BzTEACl) to give 1-difluoromethyl-2-phenylbenz- transfer catalyst was studied. Both N(1)- and N(2)-arylated imidazole 259 [75](Figure 96). products 269a and 269b, respectively, have been isolated. The N-alkylated imidazole derivatives 262 were achieved Their ratio has depended on the nature of the employed base by treating compounds 260 with different alkyl bromide and the reactivity of arylating agent [92](Figure 99). 34 Journal of Chemistry

H N N R N N N + RX N S S N N Ar− Ar−

276 277 x x F x x x x N x x + N

H NO2

NO2 278 279–288

Pyrazole, imidazole, 1, 2, 4-triazole, indazole, benzotriazole Br

− Ar n H O N N N N PTC N N + Br-(CH ) - Br N 2 n N O N O N Ar− + N N N N N Ar− n Ar− O

289 291 290

Figure 103

N N N NRCOMe O NCOMe O N NHCOMe TBMSO O N TBMSO N TBMSO RX N + N N N PTC N N R TBMSO TBMSO TBMSO OSMDBT OSMDBT OSMDBT 293b 292 293a

R = Me, PhCH2, CH2- CH = CH2, X = Br, I

Figure 104

Treatment of benzotriazole 267 with chlorodiflurometh- in 23% and 4-benzyl-1-difluoromethyl-1,2,3,5-tetrazole 275b ane under liquid-liquid conditions (CH2Cl2/aq. NaOH/ in 15% [74](Figure 102). BzTEACl) has afforded 1-(difluoromethyl)-1H-benzotriazole A series of 5-alkylthio-1-aryltetrazoles 277 were prepared 270 [74](Figure 100). by alkylation reaction of the corresponding 1-aryltetrazole- Reaction of 4-substituted-1,2,3-triazol 271 with alkyl 5-thiols 276 with alkyl bromides under solid-liquid PTC bromide 272 under basic condition using PTC Bu4NBr technique [94], whereas without solvent and also under produced N-substituted 1,2,3-triazole derivatives 273a–c [93] PTC technique several N-p-nitrophenylazoles 279–288 were (Figure 101). synthesized by direct arylation of the corresponding azolo The alkylation of 5-benzyl-1H-tetrazole 274 under liquid- compound 278 with p-fluoronitrobenzene [95], while the liquid technique such as (CH2Cl2/aq. NaOH/BzTEACl) gave alkylation reaction of 1-aryltetrazol-5-ones 289 with dibro- a mixture of 5-benzyl-1-difluoromethyl-1,2,3,5-tetrazole 275a moalkanes under both liquid-liquid and solid-liquid PTC Journal of Chemistry 35

NH2 NH2 N N N PTC N + RX N MW N H N N R

294 295

Figure 105

Cl

CH3 O O NN NN O ArO ArO + O Cl NH S NH2 S

296 297 298

Figure 106

S S Ph NH Ph N CH2

O H CH2=CH-CH2Br O H PTC

MeO MeO OMe OMe 299 300

Figure 107

R R

N P.T.C. 󳰀 + ClCH2CH2NH2 󳰀 N R 70∘C R N N H

CH2CH2NH2 301–303 304–306

󳰀 󳰀 󳰀 󳰀 301, 304 R= R = H; 302, 305 R = CH3, R = H; (a), R = CH3, R = H; (b) 303, 306 R= R = CH3

Figure 108

1 R1 R R1

P.T.C. P.T.C. N N R ClCH CH Cl N −HCl R N 2 2 R N H N CH = CH CH2CH2Cl 301–303 307–309

301, 304, 307 R= R1 = H; 302, 305, 308 R = H, R1 = Me, R = Me, R1 = H; 303, 306, 309. R, R1 = Me

Figure 109 36 Journal of Chemistry

OH HO + 2C12H25Br H25C12O OC12H25 O O

310 311

OH + Br (CH ) Br O 2 12 O O O 12

312 313

X(CH2)nX 314 O O n=1, 4, 5; X = Br O n 315

Figure 110

OMe OMe O O Crotyl O Crotyl O CH2Cl2/T.B.A.B. H Benzyl bromide/NaOH H

HO OH HO O Benzyl

316 317

Figure 111

S-(CH2)n-S S Ph Ph NNHHN N Ph N NH OMe O H Br(CH2)nBr O OMe PTC H O OMe H OMe MeO OMe 318 319a, b

Figure 112

O O O

− Ar− Ar− R Ar N BrCH2CH2Br N RX N S S S S S S

322 320 321a–h

R = Me, Et, CH2CHO, CH2CO2Et, CH(CO2Et)2, COMe, CO2Et, p-NO2-C6H4-N = N

Figure 113 Journal of Chemistry 37

CO t-Bu CO2 t-Bu N 2 N + O Br O

323 324

Figure 114

R2 O R1 N Br O O R3 N N S R2 O O O O 1 Ph R H H O N Ph + H H 3 H H R N N S O O H H O O H O O O O Ph Ph Ph Ph 325 326 327

Figure 115 systems provided a convenient route to prepare bis-tetrazolon to concurrent dehydrochlorination of 2-chloroethylamine. derivatives 290 and 4-bromoalkyl derivatives 291 [96] Theyieldwasconsiderablydecreasedingoingfrompyrazole (Figure 103). (301) to 3,5 dimethylpyrazole (303)whereasthemaximal N-Acetylated adenosine 292 was alkylated with ben- yield of alkylated products (70–80%) was obtained by zyl bromide, methyl iodide, or allyl bromide in the pres- using one of the following ratios: pyrazole : NaOH : 2- ence of tetrabutylammonium bromide as a PTC catalyst in chloroethylamine 1 : 2 : 2, 3-(5)methylpyrazole : NaOH : 2 CH2Cl2/NaOH to give the corresponding N-alkyl-6-N-acetyl chloroethylamine 1 : 3 : 3, or 3,5-dimethylpyrazole : NaOH : 2- adenosines 293a, b [97](Figure 104). chloroethylamine 1 : 5 : 5 [100](Figure 108). N-alkylation reaction of adenine 294 took place with In the N-alkylation reaction of pyrazole, 3-(5)-meth- different alkyl halides under the phase transfer conditions ylpyrazole, and 3,5-dimethylpyrazole 301–303 with dichlo- using microwave irradiation assistance [98](Figure 105). roethane (DCE), the dehydrochlorination of the obtained 1- 5-Aryloxymethyl-2-[(2-chlorophenyl)oxyacetylamido]- (𝛽-chloroethyl)pyrazoles has been carried out to give the cor- 1,3,4-thiadiazoles 280 are synthesized from reaction of responding products N-vinylpyrazoles 307–309 (Figure 9)in 2-chlorophenyloxyacetyl chloride 297 with 5-aryloxymethyl- low yield. Attempts to carry out the reaction under standard 2-amino-1,3,4-thiadiazoles 296 under liquid-liquid condition conditions (water/benzene/NaOH/TEBAC) did not lead to using PEG-400 as a catalyst [99](Figure 106). the desired result. The yield of all products was sharply N-Alkylation of 3-phenyl-2-thiohydantoin-5-arylidene increased when benzene was replaced with an excess of derivative 299 has been carried out by using monohalocom- dichloroethane. The reaction investigation showed that the pounds such as allyl bromide as an alkylating agent. The reac- ease of alkylation depends strongly on the basicity of the pyra- tion was proceeded through nucleophilic displacement under zole. The introduction of an electron-donating substituent PTC conditions of solid-liquid phases such as a mixture of (e.g., Me) into the molecule of pyrazole 301 increases the anhydrous potassium carbonate, dioxane, and TBAB as a electron density at the “pyrazole” nitrogen atoms. As a result, heterogeneous catalyst. The corresponding alkylated product deprotonation was hindered and the base was consumed in 300 was obtained in a good yield [42](Figure 107). elimination of dichloroethane. It must also be mentioned Alkylation reaction of pyrazoles 301–303 with 2- that a 5- to 7-folds excess of dichloroethane was necessary to chloroethylamine under the condition of phase-transfer obtain optimal yields on alkylation of compounds 301–303 catalysis was carried out in a liquid-solid system using [101](Figure 109). benzeneasanorganicsolventandBTEACasacatalyst. Reaction between equimolar amounts of reactants led to 5.1.2. O-Alkylation or Acylation. 2,5-Didodecyloxymethyl- poor yields (20–40%) of the alkylated products 304–306 due furan 311 was obtained via alkylation of 2,5-dihydroxym- 38 Journal of Chemistry

Ph Ph N N 1 O S O SR RX/CS2 PTC N N H SR 91 SR 328a, b (a) R1 = H, R = Et 1 (b) R = R = PhCH2

Figure 116

S S

Ph Ph COCH2Cl NNH NN

ClCH2COCl OMe OMe O O H H OMe OMe

318 329

Figure 117

Ar− CH2 − − − O Ar N Ar O Ar O N Het−H+ S Piperazine S N S Het S Br S S S S N 330 331a,b 332 N N NH HetH = a: ; b: 2 HS N OH S

Figure 118

R H C H3C 3 H3C

N + N N + RX O R O N N N Ph Ph Ph 333 334a–e 335a–e

Figure 119

NN N N N N O N (CH2)4Br () HO N 4 NH + N O O H

336 337 338

Figure 120 Journal of Chemistry 39

Ar−

− Ar N Ar− O N + F SO2Cl S Ar− N O H F 340 339 341

Ar− N Ar− O + F SO 2Cl S N O H F 342 339 343

Figure 121

H F O N H3C SO2Cl F O Cl PTC F O N F + N O O CH3 H C O 3 S O 344 345 N O CH3

346

Figure 122

O Cl N N NH + O N N Cl N 347 348 349

Figure 123

OEt O OEt P P-S-sec-Bu H N + Cl P S-sec-Bu O O S S O 350 351 352

Figure 124

O Br O

R CH2 O R O

353 354

Figure 125 40 Journal of Chemistry

CH M+ 3 H C O N CH3 3 - 2 H3C Cl N NO2 N CH3 N CH3 N 356 −HNO2 PTC N N Cl N Cl N Cl N NO 2 NO2 NO2

355 357

Figure 126

PTC + ClCH2CH2Br N N H

H2C 358 359

CH2 SH S PTC + ClCH2CH2Br N N H

H2C

360 362

N PTC N SH + ClCH2CH2Br S N N CH2 H

H2C 361 363

Figure 127

ethylfuran 310 with dodecyl bromide without solvent using or 1,3-dibromopropane afforded the thioalkylated dimers (KOH/aliquat) as a catalyst, while alkylation of furfuryl 319a, b, respectively, via s-alkylation pathway followed by alcohol 312 with 1,12-dibromododecane under the same PTC dimerization reaction [42](Figure 112). conditions produced the corresponding furanic diether 313 [102](Figure 110). 5.1.4. C-Alkylation. Reaction of 2-thiono-N(m-tolyl)thiazoli- Similarly, 2-furfuryl alcohol 312 was subjected to react din-4-one 320 with methyl bromide, ethyl bromide, chloro- with alkyl dihalides 314 using (benzene/KOH/polyethylene acetaldehyde, ethyl chloroacetate, diethyl malonate, acetyl glycol (PEG-400)) to yield the corresponding difurfuryl chloride, ethyl chloroformate, or p-nitrobenzenediazonium diethers 315 [102](Figure 110). tetrafluoroborate under solid-liquid system and using the 4-(benzyloxy)-2-[(2E)-but-2-en-1-yloxy]-5-methoxytet- heterogeneous mixture of (dioxan/K2CO3/TBAB) as a PTC rahydrofuran-3-ol 317 was obtained from benzylation of yielded the corresponding 5-substituted thiazolidin-4-ones 𝛼 𝛽 2-O-methyl-5-O-crotyl- , -D-ribofuranoside 316 using 321a–h and yielded the corresponding spiro thiazolidin-4- benzyl bromide in aq. solution of NaOH/CH2Cl2 and TBAB one derivatives 322 when reacted with 1,2-dibromoethane as a catalyst [103](Figure 111). underthesamePTCcondition[104](Figure 113). 4-Benzyl-2-phenyl-2-oxazoline-4-carboxylic acid tert- 5.1.3. S-Alkylation. PTC alkylation of arylidene derivative butyl ester 324 was prepared via the alkylation of 2-phenyl-2- 318 using dihalocompounds such as ethylene dibromide oxazoline-4-carboxylic acid tert-butyl ester 323 with benzyl Journal of Chemistry 41

− O Ar− O Ar N N ArCHO Ar− S S PTC S S 385 384

Ar = Ph, p-MeO-C6H4- 2-Thienyl- ; 2-turyl-

Figure 128

O Ar− N HCHO HO − O Ar PTC S S N 387 S S

386

O Ar− CN N Ar󳰀CH=C(CN) NC 2 S S PTC Ar󳰀 388 󳰀 Ar = Ph, 4-N(Me)2-C6H4-

Ar− − O Ar O N N N CNCH2CONH2 Ar󳰀 S PTC 󳰀 S S S Ar

390 389 󳰀 Ar = p-OMe-C6H4-; Ar = m-Me-C6H4-

Figure 129

O CHCl /NaOH R O 3 R N O Ph Ph

391 392

Cl

Cl Cl R O R N O Ph Ph

Figure 130 42 Journal of Chemistry

R R Cl TBAHSO4 R + CHCl3 NaOH N N R H 394 393 Cl Cl O

CHO Cl

TBAHSO4 R + CHCl3 N NaOH H N R

395 396

Figure 131

Me Me Me N O N O N PTC Way A S + RS-SR S O R = Me O −SO2 400 SMe SMe

CH3 Me N N O O −SMe S S Way B O − O− SMe SMe Me Me N O N −SMe −SO2 S SMe O− MeS SMe SMe

401

Figure 132

bromide using (toluene/KOH(s)/Cinchona alkaloids) as a benzyl chloride afforded 5-[bis(ethylsulfanyl)methylidene]- PTC [105](Figure 114). 2-(ethylsulfanyl)-3-phenyl-3,5-dihydro-4H-imidazol-4-one 2-Thioxo-3,5,7-trisubstituted-1-(2,3,5-tri-O-benzoyl-𝛽-D- 328a and 5-[bis(benzylsulfanyl)methylidene]-2-(benzylsulf- ribofuranosyl)pyrido[2,3-d]-pyrimidin-4(1H)-ones 327 have anyl)-3-phenyl-3,5-dihydro-4H-imidazol-4-one 328b,respec- been prepared via phase transfer ribosylation of 2-thioxo- tively [42](Figure 116). 3,5,7-trisubstituted pyrido[2,3-d]pyrimidin-4(1H)-ones 325 Acylation of imidazolones 318 using chloroacetyl chlo- with 2,3,5-tri-O-benzoyl-𝛽-D-ribofuranosyl bromide 326 in ride under PTC conditions yielded the corresponding acy- biphasesolventssuchasCH2Cl2/50% aq. NaOH using TBAB lated arylidene derivative 329 [42](Figure 117). as a catalyst [106](Figure 115). In the presence of dioxane as a solvent under PTC con- 5.1.5. Miscellaneous Alkylation. 5-Bromorhodanine deriva- ditions, one-pot reaction of 3-phenyl-2-thiohydantoin 91 tive 330 waseffectivelyusedasanalkylatingagentforsome with CS2 and halocompounds such as ethyl bromide or mono- or dianionic moieties containing S, N, or O under Journal of Chemistry 43 solid-liquid phase transfer catalysis conditions. Thus, with under the same reaction conditions N,S-divinyl derivatives 4-hydroxy-2-mercaptopyrimidine, where possible S, N, or 362 and 363 were prepared from 3-mercaptoindole 360 O sites are available, the reaction afforded the S-substituted and 2-mercaptobenzimidazole 361,respectively[109] product. With 2-aminobenzothiazole or piperazine, the reac- (Figure 127). tion yielded the corresponding N-substituted 331a, b or the disubstituted products 332 [104](Figure 118). 5.6. Condensation Reactions. Arylidenethiazolidin-4-ones InaplantostudyC-versusO-alkylationofthepyrazoline 385 were synthesized from condensation reaction of 2- derivatives, 3-methyl-1-phenyl-2-pyrazolin-5-one 333 was thiono-N-(m-tolyl)thiazolidin-4-one 384 with aromatic or treated under PTC condition with different bromoorganic heteroaldehydes under solid-liquid PTC technique [104] compounds such as benzyl bromide, 1,3-dibromopropane, (Figure 128). methyl bromoacetate, bromoacetaldehyde, or diethylacetal as alkylating agents either in the absence or the presence 5.7. Addition Reactions. Reaction of 2-thioxo-N-(m-tolyl) of carbon disulphide and afforded numerous of C- or O- thiazolidin-4-one 386 with formaldehyde or some arylid- alkylated derivatives 334a–e, 335a–e [107](Figure 119). enemalononitriles via PTC technique (dioxane/K2CO3/ Reaction of 6-hydroxy-3,4-dihydroquinoline 337 and 1- TBAB) afforded the corresponding 5-hydroxymethyl deriv- cyclohexyl-5-(4-bromo-butyl)-1,2,3,4-tetrazole 336 in a het- ative 387 or Michael type adduct 388,respectively.While erogeneous mixture of toluene/H2O, K2CO3 and TBACl the addition reaction of cyanoacetamide to 5-(p-methox- as a catalyst gave 6-[4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl) ybenzylidene)-2-thioxo-N-(m-tolyl)thiazolidin-4-one 389 butoxyl]-3,4-dihydrocarbostyril 338 in 99% purity [108] followed by condensation reaction under the same tec- (Figure 120). hnique gave 7-anisyl-6-cyano-2-thioxo-3-(m-tolyl)thiazolo 5.2. Sulphonylation. 4,5-Dihydro-3,5-diaryl-1-(4-fluoro- [4,5-b]pyridin-5-one 390 [104](Figure 129). phenylsulphonyl)pyrazoles 341 and 2-aryl-1-(4-fluor- phenylsulphonyl)indoles 343 were prepared from reaction of 5.8. Ring Expansion. Treatment of 5-alkyl(aryl)-3H-pyr- rolin-2-ones 391 with dichlorocarbene using (CHCl3/NaOH/ 4-fluorophenylsulphonyl chloride 339 with the appropriate ∘ 4,5-dihydro-3,5-diarylpyrazoles 340 or 2-arylindoles 342, BTEAB) at 20–30 C afforded the intermediates 1-alkyl- via solid-liquid phase (THF/KOH/TBAB) [107](Figure 121). 6,6-dichloro-2-azabicyclo[3.1.0]hexan-3-ones which directly N-Sulphonylation product 346 was prepared through rearranged and dehydrochlorinated to give 6-alkyl(aryl)-1- treating 2-chloro-6,6-difluro-1,3-dioxolo[4,5-f]benzimida- phenyl-5-oxohydropyridin-2-ones 392 [110](Figure 130). zole 344 with 3,5-dimethylisoxazole-4-sulphonyl chloride Also, ring transformation of indole derivatives 393 has 345 via PTC protocol (toluene/aq. K2CO3/TBAB) [109] been induced by dichlorocarbene (aq. KOH/TBABSO4H) (Figure 122). to produce 3-haloquinoline 394 in a good yield. Also, under similar conditions, reaction of 3-formyl-2-(3-chloro- 4-fluorophenyl)indole 395 with dichlorocarbene gave 3- 5.3. N-Carbonylation. Carbonyldiimidazole 349 was pre- 󸀠 󸀠 chloro-4-[2,2-dichloro-3-oxiranyl]-2-(3 -chloro-4 -fluoro- pared in 87% yield via reaction of imidazole 347 with phenyl)quinoline 396. The evolved HCl gas has been phosgene 348 under PTC condition (chlorobenzene/NaOH/ eliminated during the reaction [111](Figure 131). tributylhexadecylphosphonium bromide (TBHDPB)) [110] (Figure 123). 5.9. Ring Opening. Treatment of benzosultams 400 with dif- 5.4. N-Phosphorylation. Reaction of 1,3-thiazolidin-2-one ferent disulphides under PTC technique (CH3CN/K2CO3/ 350 with S-sec-Bu-O-Et chlorophosphorothiolate 351 in the TBAHSO4) gave the corresponding 2-methylamino-benzal- presence of NaOH and N-dodecyl-N-methylephedrinium dehyde dithioacetals 401 [24](Figure 132). bromide gave s-sec-Bu O-Et(2-oxo-3-thiazolidinyl) phos- phothiolate 352 in 84% yield [111](Figure 124). Abbreviations

𝛽 PTC: Phase transfer catalysis 5.5. Elimination Reactions. -Elimination of bromomethyl TEBACl: Triethylbenzylammonium chloride cyclic ketyl acetals 353 was carried out under solid-liquid t THF: Tetrahydrofuran phase (THF/Bu OK/Aliquat 336) to prepare the correspond- TBAB: Tetrabutylammonium bromide ing cyclic ketene acetals 354 [112](Figure 125). DMF: Dimethylformamide Reaction of 6-chloro-2-chloromethyl-3-nitroimidazo RT: Room temperature [1,2-b]pyridazine 355 with 3 equivalents of nitroalkane DMSO: Dimethyl sulfoxide anion derivative 356 under liquid-liquid PTC protocol BTEACl: Benzyltriethylammonium chloride (CH2Cl2/H2O/TBA(OH)) gave 3-nitroimidazo[1,2-b]pyrid- TBACl: Tetrabenzylammonium chloride azines 357 bearing trisubstituted ethylenic double bond TBAHSO4: Tetrabutylammonium hydrogen sulphate derivatives in a good yield [113](Figure 126). CTPPCl: Crotyltriphenylphosphonium chloride Vinylation of indole 358 with ClCH2CH2Br was achieved TBAHS: Tetrabutylammonium hydrogen sulphate under PTC condition (toluene/KOH/18-crown-6) and t-BuPz: Tert-butyl pyrazole afforded the corresponding N-vinyl derivative 359.Similarly, IPrPz: Isopropylpyrazole 44 Journal of Chemistry

TEAI: Tetraethylammonium iodide by 2-bromo carboxylic esters under solid-liquid phase-transfer PEG: Polyethylene glycol catalysis conditions,” Journal of Organic Chemistry,vol.57,no. 5, pp. 1603–1605, 1992. DCE: Dichloroethane TBHDPB: Tributylhexadecylphosphonium bromide [21] J. Casas, R. Grigg, C. Najera,´ and J. M. Sansano, “The effect of phase-transfer catalysis in the 1,3-dipolar cycloaddition TBA(OH): Tetrabutylammonium hydroxide reactions of azomethine ylides - Synthesis of substituted pro- BTEAB: Benzyltriethylammonium bromide. lines using AgOAc and inorganic base in substoichiometric amounts,” European Journal of Organic Chemistry, no. 10, pp. Conflict of Interests 1971–1982, 2001. [22] O. A. Abd Allah and A. M. El-Sayed, “Application of phase The authors declare that they have no conflict of interests. transfer catalysis in heterocyclic synthesis: synthesis of some new polyfunctional thiophenes, thiopyrans, pyridines and oxazines,” Phosphorus, Sulfur and Silicon and Related Elements, References vol. 177, no. 5, pp. 1291–1301, 2002. [1] M. Makosza and M. Fedorynski,´ “Catalysis in two-phase [23] A. K. El-Shafei, H. Abdel-Ghany, A. A. Sultan, and M. M. El- systems: phase transfer and related phenomena,” Advances in Saghier, “Synthesis of thieno (2,3-b) thiophenes and related Catalysis,vol.35,pp.375–422,1987. structures,” Phosphorus, Sulfur, and Silicon and the Related Elements, vol. 73, pp. 15–25, 1992. [2]E.V.DehmlowandS.S.Dehmlow,Phase-Transfer Catalysis, Chemie, Weinheim, Germany, 3rd edition, 1993. [24] H. Modrzejewska and K. Wojciechowski, “Synthesis and reac- tions of 3-alkylsulfanyl-1,3-dihydro-2,1-benzisothiazole 2,2- [3] C. M. Starks, C. L. Liotta, and M. Halpern, Phase Transfer dioxides,” Tetrahedron,vol.61,no.37,pp.8848–8854,2005. Catalysis: Fundamentals, Applications and Industrial Perspec- tives, Chapman and Hall, New York, NY, USA, 1994. [25] A. Khodairy, “Synthesis of fused and spiro heterocyclic com- pounds derived from 3,5-pyrazolidinedione derivatives,” Phos- [4] R. R. Nadendla, Indian Pharmacist,vol.2,p.13,2003. phorus, Sulfur and Silicon and Related Elements,vol.160,pp. [5] M. Makosza, “Phase-transfer catalysis. A general green method- 159–180, 2000. ology in organic synthesis,” Pure and Applied Chemistry,vol.72, [26] D. Bogdal and M. Warzala, “Microwave-assisted preparation no.7,pp.1399–1403,2000. of benzo[b]furans under solventless phase-transfer catalytic [6] J. Jarrouse and C. R. Hebd, Seances Acad Sci Ser C,vol.232,p. conditions,” Tetrahedron, vol. 56, no. 44, pp. 8769–8773, 2000. 1424, 1951. [27]M.Makosza,J.Przyborowski,R.Klajn,andA.Kwast,“Sim- [7] H. Rath and U. Einsele, “Uber¨ die chemische Modifizierung der ple synthesis of 2-substituted tetrahydrofuran-3-carbonitriles,” Zellulose durch Alkylierung,” Melliand Textilber,vol.40,p.526, Synlett, no. 12, pp. 1773–1774, 2000. 1959. [28] K. S. Krishna Murthy, B. Rajitha, and M. Kanakalingeswara [8] F. Bayer, German Patent, 959, 497, 1957. Rao, “Synthesis of biologically active angularly fused bisaroyl- [9]N.V.Gavaert,“Photoproduce,”BelgiamPatent,602,793,1961. benzodifurans by PTC and solvent free microwave irradiation,” [10] M. A. Iskenderov, V. V. Korshak, and S. V. Vinogradova, Indian Journal of Chemistry B,vol.42,no.2,pp.425–428,2003. Vysokomol Soedin,vol.4,p.637,1962. [29] R. D. Shah, “Phase transfer catalysis assisted thorpe reaction for [11] W. S. Port, British Patent, 912, 104, 1962. the synthesis of 3-aminothiophene-2-carboxylates,” E-Journal [12] R. W. Kay, British Patent, 916, 772, 1963. of Chemistry, vol. 8, no. 1, pp. 368–372, 2011. [30] W. He, B.-L. Zhang, Z.-J. Li, and S.-Y. Zhang, “PTC-promoted [13] S. Desikan and L. K. Doraiswamy, “Enhanced activity of Japp-Klingmann reaction for the synthesis of indole deriva- polymer-supported phase transfer catalysts,” Chemical Engi- tives,” Synthetic Communications,vol.35,no.10,pp.1359–1368, neering Science,vol.55,no.24,pp.6119–6127,2000. 2005. [14] T. Shioiri, “Chiral phase transfer catalysis,” in Handbook of [31] T. Cholakova, Y. Zagraniarsky, S. Simova, S. Varbanov, and A. Phase-Transfer Catalysis, Y. Sasson and R. Neumann, Eds., Dobrev, “A simple synthesis of dimethylphosphinyl-substituted chapter 14, Blackie Academic & Professional, London, UK, 1997. tetrahydropyrroles,” Phosphorus, Sulfur and Silicon and the [15] M. Makosza, “Two-phase reactions in the chemistry of carban- Related Elements,vol.180,no.7,pp.1721–1728,2005. ions and halocarbenes. A useful tool in organic synthesis,” Pure [32] A. Khodairy and A. M. El-Saghier, “Thieno[2,3-b]thiophenes: and Applied Chemistry,vol.43,p.439,1975. part 7.Some heterocyclization reactions with ethyl 3,4-diamino- [16] M. Makosza and I. Krylowa, “Remarks on the mechanism of 5-cyanothieno[2,3-b]thiophene-2-carboxylate,” Acta Chimica phase-transfer catalyzed carbanion generation in two-phase Slovenica,vol.58,no.2,pp.360–366,2011. systems,” Tetrahedron,vol.55,pp.6395–6402,1999. [33] M. Y. Ait Itto, A. Hasnaoui, A. Riahi, and J.-P. Lavergne, [17] H. Abdel-Ghany, A. M. El-Sayed, and A. K. El-Shafei, “Synthesis “Regioselective synthesis of new biheterocyclic triazepines,” of pyrrole, pyridinone and pyrimidinone derivatives using PTC Tetrahedron Letters,vol.38,no.12,pp.2087–2090,1997. conditions,” Synthetic Communications,vol.25,no.8,pp.1119– [34] G. Molteni, A. Ponti, and M. Orlandi, “Uncommon aqueous 1131, 1995. media for nitrilimine cycloadditions. I. Synthetic and mech- [18] C. G. Dave and V. A. Parikh, “Heterocyclization using phase anistic aspects in the formation of 1-aryl-5-substituted-4,5- transfer catalysis: a simple and convenient synthesis of 2- dihydropyrazoles,” New Journal of Chemistry,vol.26,no.10,pp. amino-1-aryl-5-oxo-4,5-dihydro-1H-pyrrole-3-carbonitriles,” 1340–1345, 2002. Synthetic Communications,vol.31,no.9,pp.1301–1306,2001. [35] B. W. LeBlanc and B. S. Jursic, “Preparation of 5-alkylthio [19] A. M. El-Sayed, Trends in Heterocycles,vol.9,p.33,2003. and 5-arylthiotetrazoles from thiocyanates using phase transfer [20] D. Albanese, D. Landini, and M. Penso, “Synthesis of 2-amino catalysis,” Synthetic Communications,vol.28,no.19,pp.3591– acids via selective mono-N-alkylation of trichloroacetamide 3599, 1998. Journal of Chemistry 45

[36] A. Ogihara, H. Sakai, N. Matsui, and H. Miyazaki, PCT [53] P. Sampath Rao, K. Vishnu Vardhan Reddy, and D. Ashok, International Applications WO0276,958 (Cl.C/32 ), 2002. “An efficient synthesis of dibenzoyl dialkyl benzodifurans under [37] P. Sharma, A. Kumar, and M. Sharma, “Generation of phase transfer catalysis conditions and their antifeedant activ- 4,6-dimethyl-5-[2-(2-methylprop-1-enyl)-1H-benzimidazol- ity,” Indian Journal of Heterocyclic Chemistry,vol.8,no.1,pp. 1-yl]pyrimidine-2(5H) -thiones under kinetically controlled 51–54, 1998. phase transfer catalysis conditions,” Journal of Molecular [54] P. Sampath Rao, K. Vishnu Vardhan Reddy, and D. Ashok, Catalysis A,vol.237,no.1-2,pp.191–198,2005. “Synthesis of 2,6-dibenzoyl-3,5-distyryl benzo (1,2-b: 5,4-b󸀠)- [38] A. M. Youssef, Egyptian Journal of Chemistry, vol. 45, p. 777, difurans as potential antifeedants,” Indian Journal of Hetero- 2002. cyclic Chemistry, vol. 7, no. 4, pp. 293–294, 1998. [39]M.F.Farhat,A.M.M.El-Saghier,M.A.Makhlouf,K.M. [55] P. Sampath Rao, K. Vishnu Vardhan Reddy, and D. Ashok, Kreddan, and A. B. Elmezoughi, “Ketene N,S-acetals in hete- “An efficient synthesis of dibenzoyl dialkyl benzodifurans under rocyclic synthesis: part 1: synthesis of N-phenyl-2-ylidene and phase transfer catalysis conditions and their antifeedant activ- 2,5-diylidene-4-thiazolidinone derivatives,” Journal of Sulfur ity,” Indian Journal of Heterocyclic Chemistry,vol.8,no.1,pp. Chemistry, vol. 28, no. 6, pp. 563–572, 2007. 51–54, 1998. [40] M. Fedorynski,´ M. Jezierska-Zięba, and B. Kąkol, “Phase trans- [56] K. S. Krishna Murthy, B. Rajitha, M. Kanakalingeswara Rao, T. fer catalysis in pharmaceutical industry—where are we?” Acta Raja Komuraiah, and S. M. Reddy, “Facile synthesis of biolog- Poloniae Pharmaceutica,vol.65,pp.647–654,2008. ically active linear bisaroyl benzodifurans by ptc and solvent [41] A. K. Khalil, “Phase-transfer catalyzed alkylation and cycloalky- free microwave irradiation,” Heterocyclic Communications,vol. lation of 2-mercaptoquinazolin-4(3H)-one,” Phosphorus, Sulfur 8, no. 2, pp. 179–186, 2002. and Silicon and the Related Elements,vol.180,no.11,pp.2533– [57] A. M. El-Sayed, H. Abdel-Ghany, and A. M. M. El-Saghier, 2541, 2005. “A novel synthesis of pyrano(2,3-c)-, 1,3-oxazino(2,3 b)- [42] M. K. Abou El-Regal, A. A. Abdalha, M. A. El-Kassaby, and A. ,1,2,4- triazolo(3,4-b)-, oxazolo(2,3-b)-, furano(3,2-c)-, and 3- T. Ali, “Synthesis of new thiohydantoin derivatives under phase substituted- (1,5)benzodiazepin-2-ones,” Synthetic Communica- transfer catalysis,” Phosphorus, Sulfur and Silicon and the Related tions,vol.29,no.20,pp.3561–3572,1999. Elements,vol.182,no.4,pp.845–851,2007. [58]A.Khodairy,H.Abdel-Ghany,A.M.El-Sayed,andH.Salah, [43] S. El-Metwally and A. K. Khalil, “Reactions of 1,3-diphenyl- “Synthesis of new fused and spiro 1,5-benzodiazepines,” Journal 2-pyrazolin-5-one and 4-amino-1,5-dimethyl-2- phenyl-1H- of the Chinese Chemical Society, vol. 50, no. 6, pp. 1195–1198, pyrazol-3(2H)-one. Synthesis of some new pyrazoles and pyra- 2003. zolones,” Acta Chimica Slovenica,vol.57,no.4,pp.941–947, [59] A. M. Soliman, A. A. Sultan, and A. K. El-Shafei, “Syn- 󸀠󸀠 2010. thesis of some new dispiro[dipyrano-(2,4󸀠:6,4 )bidithiolo(4,5- [44] O. Atsushi, S. Hiroshi, M. Nobuo, and M. Hidekazu, PCT b:4󸀠,5󸀠-e)-4,8-benzoquinones],” Monatshefte fur¨ Chemie Chem- InternationalApplications,WO0276,958,2002. ical Monthly,vol.126,no.5,pp.615–619,1995. [45] M. V.Zatsepina, T. V.Artamonova, and G. I. Koldobskii, “Tetra- [60] A. A. Sultan, “Synthesis of some condensed s-triazole hete- zoles: LII. Synthesis of functionally substituted tetrazoles from rocycles using phase-transfer catalysis technique,” Phosphorus, benzene-1,3,5-tricarboxylic acid derivatives,” Russian Journal of Sulfur, and Silicon and the Related Elements,vol.105,pp.123–127, Organic Chemistry,vol.44,no.4,pp.577–581,2008. 1995. [46] A. M. M. El-Saghier, “Simple one-pot synthesis of thieno[2,3- [61] A. M. M. El-Saghier, “A novel one-pot synthesis of polyfunc- b]thiophene derivatives under solid-liquid PTC conditions. tionally substituted thiopyrano(2,3-b)pyridine and pyrido(2,3- Useful starting material for the synthesis of biological active b)pyridine derivatives under solid-liquid phase-transfer catal- compounds,” Bulletin of the Chemical Society of Japan,vol.66, ysis,” Phosphorus, Sulfur and Silicon and Related Elements,vol. no.7,pp.2011–2015,1993. 177, no. 5, pp. 1213–1221, 2002. [47] K. C. Majumdar, S. Saha, and A. T. Khan, “Indian Journal of [62] C. Bezergiannidou-Baloucts, K. E. Litinas, E. M. Xenikaki, and ChemistryB,”vol.33,p.216,1994. D. N. Nicolaides, “Reactions of 7-(Methoxyimino)-4-methyl- [48] R. M. Butnariu and I. I. Mangalagiu, “New pyridazine deriva- 2H-chromene-2,8(7H)-dione with Phosphorus Ylides. Synthe- tives: Synthesis, chemistry and biological activity,” Bioorganic sis of 2-Substituted 6-Methyl-8H-benzopyrano[7,8-d]oxazol-8- and Medicinal Chemistry,vol.17,no.7,pp.2823–2829,2009. ones,” Liebigs Annalen Der Chemie,vol.1993,pp.1175–1177,1993. [49] A. M. El-Sayed, “One—pot synthesis of pyridines, thienopy- [63] H. A. Ghany, “Synthesis of new spiro heterocyclic compounds ridines, pyrrolothienopyridines and (1,8)naphthyridines under derived from rhodanine derivatives,” Phosphorus, Sulfur and phase-transfer catalysis conditions,” Phosphorus, Sulfur and Silicon and Related Elements, vol. 122, pp. 173–180, 1997. Silicon and Related Elements,vol.163,pp.29–40,2000. [50] A. K. El-Shafei, A. M. Soliman, A. A. Sultan, and A. M. [64] H. Abdel-Ghany, A. M. El-Sayed, A. Khodairy, and H. Salah, M. El-Saghier, “Synthesis of some new fused heterocycles “Synthesis of new 3-substituted and spiro 1,5-benzodiazepin- containing a bridgehead nitrogen atom under ptc conditions— 2-ones under phase-transfer catalysis conditions,” Synthetic a new application of cyanoketene s,s-acetals,” Gazzetta Chimica Communications,vol.31,no.16,pp.2523–2535,2001. Italiana,vol.125,p.115,1995. [65] E.Diez-Barra,A.delaHoz,A.Loupy,andA.Sanchez-Migallon, [51] A. Khodairy and A. M. El-Sayed, “Synthetic studies on the “Selective alkylation of pyrrole by phase transfer catalysis in the synthesis of pyridine, 𝛼-pyran, 𝛼-thiopyran, and Thienoth- absence of solvent,” Journal of Heterocyclic Chemistry,vol.31,pp. iopyranopyrrol derivatives using PTC technique,” Synthetic 1715–1717, 1994. Communications,vol.31,no.4,pp.475–486,2001. [66] A. Nakmura and K. Takamoto, Japanese Kokai Tokkyo Koho JP, [52]G.A.El-Saraf,A.M.El-Sayed,andA.M.M.El-Saghier, 171,379, (Cl.C07D417/12), 2003. “One-pot PTC synthesis of polyfused pyrazoles,” Heteroatom [67] A. Nakamura and K. Takamoto, Japanese Kokai Tokkyo Koho Chemistry,vol.14,no.3,pp.211–217,2003. JP,138,079,(Cl.C07D209/48),2002. 46 Journal of Chemistry

[68] G. Guazzelli and R. Settambolo, “4-Indolylbutanals from rho- [83] E. Diez-Barra, A. De La Hoz, A. Sanchez-Migallon, and J. dium-catalyzed hydroformylation of allylindoles as precursors Tejeda, “Alkylation of imidazole by solid-liquid phase transfer of benzofused indolizines,” Tetrahedron Letters,vol.48,no.34, catalysis in the absence of solvent,” Synthetic Communications, pp. 6034–6038, 2007. vol. 23, no. 13, pp. 1783–1786, 1993. [69] R. Settambolo, S. Miniati, and R. Lazzaroni, “One pot hydro- [84] X. Chen, X. Wang, H. Wang, H. Lian, Y. Pan, and Y. Shi, formylation/intramolecular aldol condensation reactions of 1- “N-alkylation of 2-methyl-2-imidazolines by phase transfer allyl-2-carbonylpyrroles: a new entry into hydroindolizines catalysis without solvent,” Synthetic Communications,vol.29, synthesis,” Synthetic Communications,vol.33,no.17,pp.2953– no. 17, pp. 3025–3030, 1999. 2961, 2003. [85] X.Chen,X.Wang,H.Wang,H.Lian,Y.Pan,andY.Shi,“Chem- [70] R. Settambolo, M. Mariani, and A. Caiazzo, “Synthesis of 1,2- Inform abstract: N-Alkylation of 2-Methyl-2-imidazolines by and 1,3-divinylpyrrole,” Journal of Organic Chemistry,vol.63, phase transfer catalysis without solvent,” Cheminform,vol.30, no.26,pp.10022–10026,1998. no. 43, 1999. [71]P.DeLaCruz,A.DeLaHoz,L.M.Font,F.Langa,andM.C. [86] E. V. Dehmlow, R. Richter, and A. B. Zhivich, Journal of Perez-Rodr´ ´ıguez, “Solvent-free phase transfer catalysis under Chemical Research S,vol.504,1993. microwaves in fullerene chemistry. A convenient preparation of [87] S. Khabnadideh, Z. Rezaei, A. Khalafi-Nezhad, R. Bahrinajafi, N-alkylpyrrolidino[60]fullerenes,” Tetrahedron Letters,vol.39, R. Mohamadi, and A. A. Farrokhroz, “Synthesis of N-alkylated no. 33, pp. 6053–6056, 1998. derivatives of imidazole as antibacterial agents,” Bioorganic and [72] I. Almena, E. D´ıez-Barra, A. De La Hoz, J. Ruiz, A. Sanchez-´ Medicinal Chemistry Letters, vol. 13, no. 17, pp. 2863–2865, 2003. Migallon,´ and J. Elguero, “Alkylation and arylation of pyrazoles [88] K. Ramaiah, P. K. Dubey, D. Eswara Rao et al., “Synthesis under solvent-free conditions: conventional heating versus and spectral properties of a variety of 2-styrylbenzimidazoles,” microwave irradiation,” Journal of Heterocyclic Chemistry,vol. Indian Journal of Chemistry B,vol.39,no.12,pp.904–914,2000. 35,no.6,pp.1263–1268,1998. [89] S. Khabnadideh, Z. Rezaei, A. Khalafi-Nezhad, R. Bahrinajafi, [73] Inc. Hoffman La-Roch, NJ. Nutely,United States Patent, Patent R. Mohamadi, and A. A. Farrokhroz, “Synthesis of N-alkylated No. US 6,326,501 B1, 2001. derivatives of imidazole as antibacterial agents,” Bioorganic and Medicinal Chemistry Letters, vol. 13, no. 17, pp. 2863–2865, 2003. [74] A. Jonczyk,´ E. Nawrot, and M. Kisielewski, “Reactions of [90] E. V. Dehmlow, J. Bollhofer, and G. Thye, “Journal of Chemical some nitrogen heterocycles with chlorodifluoromethane under Research S,” vol. 113, 2001. conditions of phase-transfer catalysis,” Journal of Fluorine Chemistry, vol. 126, no. 11-12, pp. 1587–1591, 2005. [91] A. Abenhaim, “Selective alkylations of 1,2,4-triazole and benzo- triazole in the absence of solvent,” Heterocycles,vol.38,no.4,p. [75] P. Barraja, P. Diana, A. Carbone, and G. Cirrincione, “Nucle- 793, 1994. ophilic reactions in the indole series: displacement of bromine [92]I.P.Beletskaya,D.V.Davydov,M.S.Gorovoi,andS.V. under phase transfer catalysis,” Tetrahedron,vol.64,no.51,pp. Kardashov, “Selective N(1)-arylation of benzotriazole with acti- 11625–11631, 2008. vated aryl halides under conditions of phase transfer catalysis,” [76] C. Barrett, B. Choudhury, A. Natansohn, and P. Rochon, “Azo- Russian Chemical Bulletin,vol.48,no.8,pp.1533–1536,1999. carbazole polymethacrylates as single-component electrooptic [93] C. G. Oliva, N. Jagerovic, P. Goya et al., “N-substituted- materials,” Macromolecules,vol.31,no.15,pp.4845–4851,1998. 1,2,3-triazoles: Synthesis, characterization and evaluation as [77] I. Almena, E. D´ıez-Barra, A. De La Hoz, J. Ruiz, A. Sanchez-´ cannabinoid ligands,” Arkivoc,vol.2010,no.2,pp.127–147,2010. Migallon,´ and J. Elguero, “Alkylation and arylation of pyrazoles [94] K. Waisser, J. Kunes, A. Hrabalek, M. Machacek, and Z. under solvent-free conditions: conventional heating versus Odlerova, “New groups of potential antituberculotics: 5- microwave irradiation,” Journal of Heterocyclic Chemistry,vol. Alkylthio-1-aryltetrazoles,” Collection of Czechoslovak Chemical 35,no.6,pp.1263–1268,1998. Communications,vol.61,p.791,1996. [78] F. L. Tang, Z. H. Wang, W. L. Jia, Y. M. Xu, and J. T. [95] M. L. Cerrada, J. Elguero, J. De La Fuente, C. Pardo, and M. Wang, “Synthesis of diorganotin derivatives containing asym- Ramos, “Synthesis of p-nitrophenylazoles by phase transfer metric disubstituted bis(pyrazol-1-yl)methanes: X-ray crystal 󸀠 catalysis without solvent,” Synthetic Communications,vol.23, structures of (3-isopropylpyrazol-1-yl-5 -isopropylpyrazol-1- no.14,pp.1947–1952,1993. yl)methane diphenyltin(IV) dibromide and bis(5-isopropyl- [96] Y. V. Poplavskaya, L. V. Alam, and G. I. Koldobskii, “Tetrazoles: pyrazol-1-yl)methane diphenyltin(IV) dibromide,” Polyhedron, XLI. Alkylation of 1-aryltetrazol-5-ones,” Russian Journal of vol. 19, pp. 381–387, 2000. Organic Chemistry,vol.36,no.12,pp.1793–1799,2000. [79] V. N. Pathak, C. K. Oza, R. Pathak et al., “Fluorophenylsulpho- [97] K. Aritomo, T. Wada, and M. Sekine, “Alkylation of 6-N- nylation of 4,5-dihydro-3,5-diarylpyrazoles and 2-arylindoles acylated adenosine derivatives by the use of phase transfer via solid-liquid phase transfer catalysis,” Indian Journal of catalysis,” Journal of the Chemical Society,no.14,pp.1837–1844, Heterocyclic Chemistry, vol. 7, no. 3, pp. 241–242, 1998. 1995. [80]E.Arranz,J.A.D´ıaz, E. Morante, C. Perez,´ and S. Vega, “Prepa- [98] H. Rodr´ıguez, R. Perez,´ M. Suarez,A.Lam,N.Cabrales,andA.´ ration and regiochemical assignments of new pyrazolo[3,4-c] Loupy, “Alkylation of some pyrimidine and purine derivatives [2,1] benzothiazepines,” Journal of Heterocyclic Chemistry,vol. using microwave-assisted methods,” Heterocycles,vol.55,no.2, 33,no.1,pp.151–156,1996. pp.291–302,2001. [81]M.L.Taha,H.B.Lazrek,J.L.Barascut,andJ.L.Imbach, [99] L. Zheng, W. Xi-cun, Y. Jing-ya, and Z. Kexueban, Journal of “Synthesis of some 4-substituted 1-[(2-hydroxyethoxy)methyl]- Northwest Normal University,vol.37,p.54,2001. pyrazolo[3,4-d]pyrimidines,” Bulletin des Societ´ es´ Chimiques [100] O. S. Attaryan, A. O. Baltayan, R. E. Sagatelyan, and K. Belges,vol.105,pp.279–285,1996. T. Takmazyan, “Synthesis of 1-(2-aminoethyl)pyrazoles under [82]H.B.Lazrek,M.Taourirte,J.L.Barascut,andJ.L.Imbach, phase-transfer catalysis,” Russian Journal of General Chemistry, Bulletin Des Societ´ es´ Chimiques Belges,vol.105,p.391,1996. vol.78,no.1,pp.136–138,2008. Journal of Chemistry 47

[101] O. S. Attarian, S. G. Matsoyan, and S. S. Martirosyan, “Synthesis of N-vinylpyrazoles,” Chemistry of Heterocyclic Compounds,vol. 41, no. 4, pp. 452–455, 2005. [102]M.Majdoub,A.Loupy,A.Petit,andS.Roudesli,“Coupling focused microwaves and solvent-free phase transfer catalysis: application to the synthesis of new furanic diethers,” Tetrahe- dron,vol.52,no.2,pp.617–628,1996. [103]T.M.Slaghek,A.H.vanOijen,A.A.M.Maas,J.P.Kamerling, and J. F. G. Vliegenthart, “Synthesis of structural elements of the capsular polysaccharides of Streptococcus pneumoniae types 6A and 6B,” Carbohydrate Research,vol.207,no.2,pp.237–248, 1990. [104]A.K.El-Shafei,A.M.El-Sayed,A.A.Sultan,andH.Abdel- Ghany, Gazzetta Chimica Italiana,vol.120,p.197,1990. [105] S.-S. Jew, Y.-J. Lee, J. Lee et al., “Highly enantioselectlve phase-transfer-catalytic alkylation of 2-phenyl-2-oxazoline-4- carboxylic acid tert-butyl ester for the asymmetric synthesis of 𝛼-alkyl serines,” Angewandte Chemie - International Edition, vol. 43, no. 18, pp. 2382–2385, 2004. [106] T. Tamura and E. Ryukoku, Japanese Kokai Tokkyo Koho JP,128, 688 (Cl. CO7F 9/6539), 2003. [107]S.A.Shiba,N.S.Harb,M.El-Kassaby,M.A.Hassan,andN. M. Abouelregal, “Facile synthesis of 4-substituted 2-pyrazolin- 5-ones under phase transfer catalysis,” Phosphorus, Sulfur, and Silicon and the Related Elements,vol.104,pp.15–20,1995. [108] USPTO Applicaton #: #20090176826—Class: 514312 (USPTO). [109]E.Abele,O.Dzenitis,K.Rubina,andE.Lukevics,“Synthesisof N- and S-vinyl derivatives of heteroaromatic compounds using phase-transfer catalysis,” Chemistry of Heterocyclic Compounds, vol. 38, no. 6, pp. 682–685, 2002. [110] A. Yu Egorova, V. A. Sedavkina, and Z. Y. Temofeyeva, “Inter- action of 1,5-substituted pyrrolin-2-ones with dichlorocarbene under phase transfer catalysis conditions,” Molecules,vol.5,pp. 1082–1084, 2000. [111] C. I. Krishna, J. Renuka, and S. Arora, Journal of the Indian Chemical Society,vol.70,p.567,1993. [112] W. J. Bailey and L.-L. Zhou, “A new elimination with phase- transfer catalysis for cyclic ketene acetals,” Tetrahedron Letters, vol.32,no.12,pp.1539–1540,1991. [113] T. Terme, C. Galtier, J. Maldonado, M. P. Crozet, A. Gueiffier, and P. Vanelle, “Synthesis of 2-substituted-3-nitroimidazo[1,2- b]pyridazines as potential biologically active agents,” Journal of Heterocyclic Chemistry,vol.39,no.1,pp.173–177,2002. International Journal of International Journal of Organic Chemistry International Journal of Advances in Medicinal Chemistry International Photoenergy Analytical Chemistry Physical Chemistry Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

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