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2-Amino-4-thiazolidinones: synthesis and reactionsM. A. Metwallya; Abdelbasset A. Farahatbc; Bakr F. Abdel-Wahabd

a Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, Egypt b Departmentof Chemistry, Georgia State University, Atlanta, GA, USA c Department of Pharmaceutical OrganicChemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt d Department of Chemistry,Faculty of Science & Arts, King Abdulaziz University, Khulais, Saudi Arabia

Online publication date: 12 August 2010

To cite this Article Metwally, M. A. , Farahat, Abdelbasset A. and Abdel-Wahab, Bakr F.(2010) '2-Amino-4-thiazolidinones: synthesis and reactions', Journal of Sulfur Chemistry, 31: 4, 315 — 349To link to this Article: DOI: 10.1080/17415993.2010.482155URL: http://dx.doi.org/10.1080/17415993.2010.482155

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Journal of Sulfur ChemistryVol. 31, No. 4, August 2010, 315–349

REVIEW ARTICLE

2-Amino-4-thiazolidinones: synthesis and reactions

M.A. Metwallya*, Abdelbasset A. Farahatb,c and Bakr F. Abdel-Wahabd

aDepartment of Chemistry, Faculty of Science, Mansoura University, P.O. Box 23, Mansoura, Egypt;bDepartment of Chemistry, Georgia State University, Atlanta, GA 30303, USA; cDepartment of Pharmaceu-tical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; dDepartmentof Chemistry, Faculty of Science & Arts, King Abdulaziz University, Khulais, Saudi Arabia

(Received 9 January 2010; final version received 28 March 2010 )

Methods for the synthesis of 2-amino-4-thiazolidinones and their chemical properties are reviewed forthe first time. 2-Amino-4-thiazolidinones are synthetically versatile substrates, as they can be used for thesynthesis of a large variety of biologically active compounds, such as thiazolodihydropyrazoles, thiazolo-triazines, and thiazolotetrahydropyrimidones, and as a raw material for drug synthesis. The high reactivityof amino and active methylene groups next to the carbonyl of the thiazolidin ring represents useful targetsfor many organic reactions.

Keywords: thiazolidine; 5-ones; synthesis; reactions; applications

1. Introduction

Amino-4-thiazolidinones, or their tautomeric forms, named pseudothiohydantoin have encoun-tered a prominent place in heterocyclic chemistry, due to the high practical value of these com-pounds, and the broad spectrum of their biological activities. For example, 2,4-dioxothiazolidinederivatives are useful as hypoglycemics and hypolipidemic agents (1), and as intermediates inthe synthesis of antidiabetic drugs (2). Other compounds derived from 2-amino-4-thiazolidinonesare used as anticancer agents (3, 4), antiproliferative (5), antiinflammatory (6), cardiotonic (7),tuberculostatic (8, 9) and as dual 5-lipoxygenase and cyclooxygenase inhibitors with antiinflam-matory activity (10). Despite this versatile importance, 2-amino-4-thiazolidinones have not beenpreviously reviewed. The main purpose of this review is to present a survey of the chemistry of2-amino-4-thiazolidinones and provide useful and up-to-date data for medicinal chemists.

2. Synthesis of 2-amino-4-thiazolidinones

2.1. From α-halo carboxylic acid derivatives

2-Imino-4-thiazolidone HCl 1 was synthesized from ethyl chloroacetate and thiourea in 95%ethanol, neutralization in sodium acetate solution under reflux gave 2-imino-4-thiazolidone 2

*Corresponding author. Email: [email protected]

ISSN 1741-5993 print/ISSN 1741-6000 online© 2010 Taylor & FrancisDOI: 10.1080/17415993.2010.482155http://www.informaworld.com

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316 M.A. Metwally et al.

(Scheme 1) (11–15).

H2N NH2

S

+ Cl CO2Et

95%EtOH

92%

N

S NH2

OHCl AcONa, water

84%

N

S NH2

O

1 2

NH

S NH

O

2

Scheme 1. Synthesis of 2-imino-4-thiazolidone.

5-Phenyl-2-amino-4-thiazolinone 3 has been synthesized from ethyl 2-chloro-2-phenylacetate,thiourea, and anhydrous sodium acetate in ethanol (Scheme 2) (16).

CO2EtPh

Cl

H2N

S

NH2

anhd. AcONa

EtOH S

N O

H2N

Ph3

Scheme 2. Route to 5-Phenyl-2-amino-4-thiazolinone.

Treatment of 2-chloroesters 4 with thiourea afforded 2-aminothiazolidin-4-ones 5 (Scheme 3)(17, 18).

Ar

Cl

CO2Methiourea

55–65%

N

S

O

H2NAr

Ar=[2,4-(OEt)2; 3,4-Me2; 4-Cl-3-MeO; 3,5-(MeO)2; 4-NHCOMe,3-MeO]phenyl

4 5

Scheme 3. Synthesis of 2-aminothiazolidin-4-ones.

Oxiranyl- and thiiranyl-substituted 2-imino-thiazolidine-4-ones 7 (Scheme 4) were preparedby refluxing thiourea with ethyl 2-chloro-3-(oxiran-2-yl)propanoate (6, X=O) or ethyl 2-chloro-3-(thiiran-2-yl)propanoate (6, X=S) (19).

HN

S

O

HN

XO

X

EtO

Cl

S

NH2H2N +

6 7

X = O, S

Scheme 4. Synthesis of substituted 2-imino-thiazolidine-4-ones.

2-[(2-Amino-4,5-dihydro-4-oxothiazol-5-yl)methyl]isothiourea 9 was obtained upon treatmentof methyl 2,3-dibromopropanoate 8 with thiourea (Scheme 5) (19).


Journal of Sulfur Chemistry 317

OMeO

BrBr

thiourea

75%

N

SH2N

O

S

NH

NH2x 2HBr

98

Scheme 5. Synthesis of isothiourea.

Long-chain-substituted 2-imino-4-thiazolidinones and 2,4-thiazolidinediones 11 were pre-pared in about 80% yield by condensation of α-bromo-carboxylic acids 10 with thiourea(Scheme 6) (20).

Br

HO2C (CH2)n

Me thioureaNHS

O

NH

n(H2C)

Me

1011

n = 13, 15, 19

Scheme 6. Synthesis of 2-imino(oxa)-4-thiazolidinones.

Reaction of 2-bromo-3-aminopropionic acid 12 with thiourea in AcOH gave 53% thioureaderivative 13, which upon treatment with HBr gave 76% thiazoline derivative 14 (Scheme 7) (21).

OHO

NH2.HBrBr thiourea/AcOH

53%

OOH

.H2N SNH

NH2

HBr N

SH2N

O

NH2

76%

.2HBr

12 4131HBr

Scheme 7. Synthesis of thiazoline derivative.

5,5-Dialkyl-2-imino-4-thiazolidones 16 were prepared by condensing thiourea with dialkyl-substituted bromoacetic acids or the acid chlorides 15 (Scheme 8) (22).

X = OH, Cl; R1/R2 = Et/Et, Et/Pr, Et/iso-Bu, Et/sec-Bu, ethyl/1-methylbutyl

thiourea, AcONa, EtOH

N

SH2N

O

R1R2

6151

R2R1Br

H3CO

X CH3

Scheme 8. Synthesis of 5,5-dialkyl-2-imino-4-thiazolidones.

5,5-Disubstituted-2-imino-4-thiazolidones 18 were prepared by refluxing of α-bromoacidchlorides 17 with thiourea in glacial acetic acid (Scheme 9) (23).

OClEt

R Br

R = Et, Bu

thiourea, AcOH

77–84%

N

SH2N

O

R

Et

1718

Scheme 9. Synthesis of 5,5-disubstituted-2-imino-4-thiazolidones.



Reaction of α-bromo acetyl bromide and thiourea afforded 2-amino-4-thiazolidinone 2 in 25%yield (Scheme 10) (24).

S

NH2H2N+

O

BrBr

80 °C, 3 h

25%

N

S NH2

O

2

Scheme 10. Route to 2-amino-4-thiazolidinone 2.

Refluxing ethyl 6-(benzamido)-2-bromohexanoate 19 with thiourea in ethanol gave theiminothiazolidinone 20 (Scheme 11) (25).

O

EtO

HN

O

Ph

Br

S

H2N NH2+

EtOH, reflux, 20 min

69% NH

O

Ph

HN

S

O

HN

19 20

Scheme 11. Synthesis of iminothiazolidinone.

The synthesis of 5-[4-(pyridylalkoxy)benzyl]-2,4-thiazolidinediones 22, which have hypo-glycemic and hypolipidemic activities, was described. Thus treatment of α-bromoesters21 with thiourea in the presence of sodium acetate afforded 2-amino-4-thiazolidinones 22(Scheme 12) (26).

Br

MeO2C

O

R2

N

R

R1

S

NH2H2N

AcONa O

R2

N

R

R1NS

O

H2N

21 22

Scheme 12. Synthesis of 2-amino-4-thiazolidinones.

α-Bromoester 23 underwent cyclocondensation with thiourea to give the imino compound 24(Scheme 13) (27).

N

Et

OBr

MeO2Cthiourea

N

Et

OS

N

O

H2N23 24

Scheme 13. Synthesis of imino compound.

Ethyl 2-chloro-3-[4-(2-methyl-2-phenylpropoxy)phenyl]propionate 25 was condensed withthiourea followed by hydrolysis using HCl to give 5-[4-(2-methyl-2-phenylpropoxy)benzyl]thiazolidine-2,4-dione 27 which possess hypoglycemic and hypolipidemic activities(Scheme 14) (28).

OEtOOMe

Ph

Me

Cl

thiourea OOMe

Ph

Me

S

N

NH2

H2O/HCl

sulfolane

OOMe

Ph

Me

S

NH

O

25 26 27

Scheme 14. Synthesis of (AL-321).



Reaction of α-haloester 28 with thiourea in the presence of sulfolane afforded 2-((4-((2-amino-4-oxo-4,5-dihydrothiazol-5-yl)methyl)phenoxy)methyl)-2,5,7,8-tetramethylchroman-6-ylacetate 29 and 2-((4-((2,4-dioxothiazolidin-5-yl)methyl)phenoxy)methyl)-2,5,7,8-tetramethyl-chroman-6-yl acetate 30 in 26% and 39% yields, respectively (Scheme 15) (29).

O

MeO

MeMe

Me

AcO

Cl

CO2Etthiourea,sulfolane O

Me

O

MeMe

Me

AcON

S NH2

O

26%

O

MeO

MeMe

Me

AcONH

S O

O

39%

2829

30

Scheme 15. Synthesis of tetramethylchroman-6-yl acetates.

2-Phenylbenzo[d]oxazol-5-amine 31 was converted to 2-amino-5-((2-phenylbenzo[d]oxazol-5-yl)methyl)thiazol-4(5H)-one 32, upon treatment with methyl acrylate followed by reaction withthiourea (Scheme 16) (30).

O

NPh

H2N1. methyl acrylate, HCl,CuO, Me2CO

2. thiourea, NaOAc

O

NPh

S

NO

NH2

31 32

Scheme 16. Synthesis of thiazol-4(5H )-one.

1-Carbaniloyl-2-oxo-3-pyrrolidinecarboxylates 33 were brominated to give 34. These under-went substitution and cyclization reactions with thiourea to give spiro[pyrrolidinethiazolidine] 35in 29–40% yields (Scheme 17) (31).

N

O

CO2EtO

NHR

Br2/CCl2 N

O

CO2EtO

NHR

Brthiourea/EtOH

29–40%

S

N

H2N

O

N

O O

NH

R

33 5343

Scheme 17. Synthesis of spiro[pyrrolidinethiazolidine].

Methyl 3-(7-(benzyloxy)quinolin-3-yl)-2-bromopropanoate 36 was cyclocondensed withthiourea in the presence of AcONa in ethanol under reflux for 7 h to give 86% 2-imino-5-[(7-benzyloxy-3-quinolyl)methyl]thiazolidin-4-one 37 which has an antihyperglycemic effect(Scheme 18) (32).

O

O

BrN

OPh

Me +

S

H2N NH2

EtOH, reflux, 7 h

86%

S N

ON

OPh

H2N

36 37

Scheme 18. Synthesis of thiazolidin-4-one.



2-Aminothiazol-4(5H)-one 39 was prepared in 82% by reaction of α-chloro-ester 38 withthiourea in ethanol in the presence of sodium acetate (Scheme 19) (33).

NS

O

H2N

H2C

ON

Me

NCl

O

ON

Me

N

EtO

S

H2N NH2

AcONa/EtOH82%38 39

Scheme 19. Synthesis of 2-aminothiazol-4(5H )-one.

Thiazolidin-4-one 41 of hypoglycemic and hypolipidemic properties was prepared bytreatment of ethyl 2-chloro-3-(4-(2-phenylpropan-2-yloxy)phenyl)propanoate 40 with thiourea(Scheme 20) (34).

OPh

MeMeCl

CO2Et

thiourea

O

Ph

Me

MeS

N

O

H2N40 41

Scheme 20. Synthesis of thiazolidin-4-one.

Reaction between 2,9,10-tribromostearic acid 42 and thiourea afforded amino thiazolidinone43 (Scheme 21) (35).

(CH2)7

CH3O

HO

Br

Br

Br

thiourea (H2C)7CH3

O

Br Br

S

N NH2

42 43

Scheme 21. Synthesis of aminothiazolidinone.

Reaction of ethyl 4-bromo-5-oxo-3-phenyl-4,5-dihydroisoxazole-4-carboxylate 44 withthiourea afforded 2-amino-9-phenyl-7-oxa-1-thia-3,8-diazaspiro[4.4]nona-2,8-diene-4,6-dione45 (Scheme 22) (36).

NO

Ph

O

EtO2C Br

+

S

H2N NH2

KF/DMF

H2O71%

N

OS

N

O

NH2

Ph

O44 45

Scheme 22. Synthesis of 3,8-diazaspiro[4.4]nona-2,8-diene-4,6-dione.

α-Bromocarbonyl compound 46 reacted with thiourea to give thiazole derivative 47(Scheme 23) (37).

MeO2CCO2Me

Br

thiourea N

SH2N

O

CO2Me46 47

Scheme 23. Synthesis of thiazole derivative.



2-Alkyl/arylimino-5-carbethoxythiazolidin-4-ones 49 have been synthesized by the interactionof thiocarbamides 48 with diethyl bromomalonate (Scheme 24) (38).

CO2Et

CO2EtBr+

S

NH2NH

R

HN

S

O

CO2Et

N

R

NH4OH / H2O

R = H, Me, Ph, 4-MeC6H4, 4-ClC6H4, 2-MeOC6H4

48 49

Scheme 24. Synthesis of 2-subs.imino-5-carbethoxythiazolidin-4-ones.

Condensation of diethyl 2-chloro-2-arylmethylmalonates 50 with thiourea afforded 2-aminothiazolidin-4-one derivatives 51 (Scheme 25) (17).

Ar O

O OEtOEt

Clthiourea N

SH2N

O

Ar20–30%

Ar = [2,4-diethoxy; 3,4-dimethoxy; 3-ethoxy,4-hydroxy; 3-chloro,4-hydroxy,5-methoxy]phenyl

50 51

Scheme 25. Synthesis of 2-aminothiazolidin-4-one derivatives.

Phthalic anhydride was allowed to react with 3-aminopropanoic acid to give 3-(1,3-dioxoisoindolin-2-yl)propanoic acid 52, which upon bromination followed by reaction withthiourea afforded 2-[(2-amino-4-oxo-4,5-dihydrothiazol-5-yl)methyl]isoindoline-1,3-dione 53.Hydrolysis of 53 in the presence of hydrobromic acid gave 2-amino-5-(aminomethyl)thiazol-4(5H)-one 54 (Scheme 26) (21).

O

O

O

+ H2N CO2H N

O

O

CO2H1.P, Br22.HBr/H2O

3. thiourea, AcOHN

O

O

NS

O

NH2

HBr, H2O, BuOH

C6H676%

H2N NS

O

NH2

5253

54

Scheme 26. Synthesis of 2-amino-5-(aminomethyl)thiazol-4(5H )-one.

Substituted S-(1-phenylpyrrolidin-2-on-3-yl)isothiuronium salts 56 in weakly basic mediaunderwent intramolecular recyclization reaction in which the γ -lactam cycle is split and athiazolidine cycle 57 is formed (Scheme 27) (39–41).

N

OR1

Br +

S

R3HN NHR2N

OR1

S NR2

NHR3

x HBr

weak base

HN

R1S

N

O

R2

NR3

R1 = NO2, MeO; R2, R3 = H, Me

5556

57

Scheme 27. Synthesis of thiazolidine.



2.2. From chloroacetamides

Method for the removal of chloroacetyl groups is used for the preparation of 2-imino-4-thiazolidinone. Thus, 1-adamantyl methyl amine 58 was acylated with chloroacetyl chloride togive the corresponding amide 59, which was then treated with thiourea to give 2-aminothiazol-4(5H)-one 2 in addition to the recovering of the starting material as a by-product (Scheme 28) (42).

H2N ClCH2COCl NH

O

Clthiourea

58%

N

S NH2

O

58 59 2

+

H2N

Scheme 28. Pathway to 2-aminothiazol-4(5H )-one.

2-(2-(2-Chloroacetamido)acetamido)acetic acid 60 was treated with thiourea to give a mix-ture of 2-(2-aminoacetamido)acetic acid 61 and 2-aminothiazol-4(5H)-one 2. While 4-(2-chloroacetyl)piperazine-1-carbaldehyde 62 gave a mixture of piperazine-1-carbaldehyde 63 and2-aminothiazol-4(5H)-one 2 (Scheme 29) (43).

O

Cl

NH

O

HN CO2H thiourea

EtOHH2N

O

HN CO2H +

N

S NH2

O

N

N

O

Cl

CHO

thiourea

EtOH, water

N

S NH2

ON

NH

CHO

+

2

2

60 61

62 63

Scheme 29. Synthesis of 2-aminothiazol-4(5H )-one.

Condensation of 2-chloro-N ,N -dipropylacetamide 64 with thiourea in ethanol gave 2-amino-4-thiazolidinone 2 as a side product (Scheme 30) (44, 45).

O

ClN

thiourea/EtOHNH +

86%64

N

S NH2

O

2

Scheme 30. Synthesis of amino-4-thiazolidinone.

2-Imino-4-thiazolidinones 66 were prepared by reaction of thiourea derivatives with N -(2-chloroacetyl)tetrahydroisoquinoline 65 (Scheme 31) (46).



N

O

Cl

S

NH

NH

R2 R1+acetone, reflux N

S NR2

R1O

R1, R2 = H, alkyl, allyl, aryl65

66

Scheme 31. Synthesis of 2-Imino-4-thiazolidinones.

2.3. From cyanamide

Cyclocondensation of methyl 2-mercaptoacetate with cyanamide in methanol containing triethy-lamine afforded 2-amino-4-thiazolidinone 2 (Scheme 32) (47).

O

OMeHS + NH2NC

MeOH/Et3N N

S NH2

O

2

Scheme 32. Synthesis of 2-amino-4-thiazolidinone.

Heating thiolactic acid with cyanamide in water/ammonium hydroxide gave NH3 gas and aprecipitate of 82% 2-imino-4-oxo-5-methylthiazolidine 67 (Scheme 33) (48).

SH

CO2HMe

H2N CN

H2O/NH4OH82%

N

S

O

MeH2N

67

Scheme 33. Synthesis of 2-imino-4-oxo-5-methylthiazolidine.

2.4. From α,β-unsaturated carboxylic acids

Single-stage synthesis of 5-aroylmethyl-2-iminothiazolidin-4-ones 69 was achieved by reactionbetween β-aroylacrylic acids and thiourea. Thus, hydrochlorides, hydrobromides, and sulfates of69 were prepared in good yields by cyclocondensation of β-aroylacrylic acids 68 with thioureain the presence of the appropriate HX (Scheme 34) (49).

O

R CO2H +

S

H2N NH2

HX NH

S

O

NHR

Ox HX

R = Ph, p-MeC6H4, p-BrC6H4, p-ClC6H4, 5,6,7,8-tetrahydro-2-naphthyl; X= Br, Cl, HSO4

53–94%

68 69

Scheme 34. Synthesis of sulfates.

N -(maleoylamino)benzoic acids 70 were treated with thiourea derivatives to give thiazolidines71 (Scheme 35) (50).



HN

O CO2H

R

+

S

H2N NH

R1. AcONa/Ac2O

2. dioxane

HN

S

O

NR1

O

NH

R

R = 2-, 3-, or4-CO2H; R1 = Ph, H70

71

Scheme 35. Synthesis of thiazolidines.

Reactions of thiourea with, maleic acid, fumaric acid, methyl hydrogen fumarate, or its sodiumsalt give 2-imino-2,3,4,5-tetrahydro-1,3-thiazol-5-acetic acid 72, its methyl ester 73 was preparedby heating in methanol in the presence of concentrated HCl (Scheme 36) (51).

S

HN O

OHHN

OOHO

OH

O

OHO

HO

O

OHO

O

Me

O

ONaO

O

Me

S

NH2H2N

60–85%

MeOH/HCl

78%

S

HN O

OMeHN

72

73

Scheme 36. Synthesis of methyl 1,3-thiazol-5-acetic acid ester.

Dimethyl acetylene-dicarboxylic esters (DMADCs) have been treated with thiourea to give(E)-methyl 2-(2-amino-4-oxothiazol-5(4H)-ylidene)acetate 74 (Scheme 37) (52, 53).

CO2MeMeO2Cthiourea, MeOH

91%

N

S

O

H2NOMe

O

74

Scheme 37. Synthesis of (E)-methyl 2-(2-amino-4-oxothiazol-5(4H )-ylidene)acetate.

2.5. From anhydrides or imides

Maleic anhydrides 75 reacted with thiourea to give 1,3-thiazolidine 76 (Scheme 38) (51).

O O

O

R

thiourea N

S

O

H2N CO2H

R= H, Me, Ph R75 76

Scheme 38. Synthesis of 1,3-thiazolidine.



Reaction of 2,3-dibromosuccinic anhydride or bromomaleic anhydride 77 and thiourea gave(E)-2-(2-amino-4-oxothiazol-5(4H)-ylidene)acetic acid 78 (Scheme 39) (54).

OO

O

BrR

thiourea

41% R= Br10% R= H

N

S

O

H2NCO2H

8777

Scheme 39. Synthesis of (E)-2-(2-amino-4-oxothiazol-5(4H )-ylidene)acetic acid.

1-o-Tolyl-1H -pyrrole-2,5-dione 79 was reacted with thiourea to give 2-(2-amino-4-oxo-4,5-dihydrothiazol-5-yl)-N -o-tolylacetamide 80 in good yield (Scheme 40) (51).

N OO

Me thiourea

81%N

S

NH2O

O

NH

Me

79 80

Scheme 40. Synthesis of 2-(2-amino-4-oxo-4,5-dihydrothiazol-5-yl)-N -O-tolylacetamide.

When a buffer solution of N -ethylmaleimide and thiourea was left for 2 days at room temper-ature, N -ethyl-α-(2-imino-4-oxothiazolidin-5-yl)acetamide 81 was obtained (Scheme 41) (55).

NO O

Et

thiourea, KH2PO4

water74%

N

S

OO

NH

EtH2N

81

Scheme 41. Synthesis of N -ethyl-α-(2-imino-4-oxothiazolidin-5-yl)acetamide.

N-substituted maleimides were condensed with thiourea derivatives to give 4-thiazolidonederivatives 82 in 46–71% yields (Scheme 42) (56).

N

R

OO +

O

NH

NH

R1 R2 N

S

R2

R1O O

NH

R

R= Et, Ph; R1=R2=H, R1= H, R2= Ph, R1=R2=Ph82

Scheme 42. Synthesis of 4-thiazolidone derivatives.

2.6. From epoxides

The nucleophilic ring opening of gem-dicyano epoxides by N-substituted or N,N′-disubstitutedthioureas leads to 2-imino-4-thiazolidinones, via postulated cyanocarbonyl intermediates. Thus,reaction of 2,2-dicyano-3-phenyloxirane 83 and diphenylthiourea gave 55% diphenylthiazolidi-none 84 (Scheme 43) (57).



O

PhNC

NC+

S

NH

NH

Ph Ph NS

OPh

NPh

Ph

55%

8384

Scheme 43. Synthesis of diphenylthiazolidinone.

Methyl E-2,3-epoxyhexadecanoate 85 reacted with thiourea to give aminotridecylthiazo-linecarboxylate 88 and tridecylmethylenethiazolinone 89 along with Z- and E-86 and 87(Scheme 44) (58).

(CH2)12Me

O

OO

Me

thiourea, DMFO

H3C (CH2)12

Me O

MeO(CH2)12

Me

30% 5%

+

N

S

O

H2N

CH

(CH2)12

MeN

SH2N

CH

(CH)12

CO2Me

32%18%

+

85

86 87

88 89

Me

Scheme 44. Synthesis of thiazolinecarboxylate and thiazolinone.

The reaction of Z-methylepoxysuccinic acid with thiourea gave 2-imino-4-oxothiazolidine 78(Scheme 45) (59).

O

HO2C CO2Hthiourea, MeOH

75%

N

S

O

H2NCO2H

78

Scheme 45. Synthesis of 2-imino-4-oxothiazolidine.

Ethylene oxide 90 and thiourea in MeOH, kept for 2 weeks at 30 ◦C, gave 2-amino-4-keto-5-isopropylidene-2-thiazoline 91 in 92% yield (Scheme 46) (60).

OMe

MeCO2Me

thiourea/MeOH

92%

N

S

O

H2N Me

Me90 91

Scheme 46. Synthesis of 2-amino-4-keto-5-isopropylidene-2-thiazoline.

Reactions of 3-chloropentafluoropropene-1,2-oxide with thiourea gave 2-amino-5-(chlorodi-fluoromethyl)-5-fluorothiazol-4(5H)-one 92 (Scheme 47) (61).



CF2Cl

OF

F

F +

S

H2N NH2

NaHCO3, NaOH

32%

N

S

OH2N

F

CF2Cl92

Scheme 47. Synthesis of 5-fluorothiazol-4(5H )-one.

2.7. From azoalkenes

Thiourea easily reacted under very mild conditions with some conjugated azoalkenes 93 in a one-pot reaction to give 39–88% of substituted thiazolinones 94 that frequently exhibited hydrazono-hydrazino tautomerism in the chain at position 5 of the ring. The chemical structure was confirmedby x-ray diffraction (Scheme 48) (62).

O

XRNN

CH3O

MeO +S

H2N NH2

MeOHN

S

O

H2N

N

Me

NH

O

XR

69–88%

XR= NH2, NHPh, OMe93

94

Scheme 48. Synthesis of substituted thiazolinones.

2.8. From isothiourea derivatives

2-Amino-4-oxy-5-aminomethyl(ethyl)thiazolines, which have radioprotective activity, were syn-thesized. 2-Amino-4-oxo-5-aminomethyl-2-thiazoline dihydrobromide (96, n = 0) and 2-amino-4-oxo-5-aminoethyl-2-thiazoline dihydrobromide (96, n = 1) were prepared by cyclization of S-(1-carboxy-2-aminoethyl)isothiourea (95, n = 0) and S-(1-carboxy-3-aminopropyl)isothiourea(95, n = 1), respectively (Scheme 49) (63).

SCO2H

n(H2C)

NHH2N

NH2

76-80%S

n(H2C)

NH2N

NH2

O

x 2HBrx 2HBr

95 96

Scheme 49. Synthesis of 2-thiazoline.

Synthesis of 2-substituted E-5-arylidenethiazolin-4-ones 98 from α,β-unsaturated acyl isoth-iocyanates was reported. Thus, propenoylthioureas 97 were oxidized with bromine in chloroformto E-5-arylidenethiazolin-4-ones 98 (Scheme 50) (64).

R

O

NH

S

NH2

S

NH2N

O

RBr2 /CHCl3

70–76%

R = Ph, 2-furyl 8979

Scheme 50. Synthesis of E-5-arylidenethiazolin-4-ones.



2.9. From 2-(alkylthio)-2-thiazolin-4-ones

Reactions of E-5-(arylmethylene)-2-(alkylthio)-2-thiazolin-4-ones 99 with ammonium carbonatewere reported to give 100 while reaction with aromatic primary amine and secondary aminesafforded 101 and 102 (Scheme 51) (65).

N

S

O

MeS

R

(NH4)2CO3

N

S

O

H2N

R

ArNH

R = 2-Cl, 4-Cl, 2-MeO, 3-MeO, 4-MeO;Ar = H, 4-MeC

6H4, 4-MeOC

6H

4, PhCH2, 4-MeC

6H

4CH

2, 4-MeOC

6H

4CH

2; X= CH

2, O

2N

S

O

NH

R

Ar

X

NH

N

S

O

N

R

X

99

100

101

102

Scheme 51. Synthesis of E-5-(arylmethylene)-2-thiazolin-4-ones.

2.10. Miscellaneous methods

Reaction of ethyl thiocyanoacetate with aromatic aldehydes in the presence of thioureas affordedE-5-arylidene-2-imino-4-thiazolidinones 103 (Scheme 52) (66).

O

SOEtNC

1. thiourea

2.ArCHO, EtOH

N

S

O

H2N Ar

(p-Me, o-MeO, p-NMe2)C6H4103

Scheme 52. Synthesis of E-5-arylidene-2-imino-4-thiazolidinones.

2-Iminothiazolidin-4-one 104 derivative was prepared in two steps. 1,2-Diethoxybenzene wascondensed with ethyl (chlorocarbonyl)formate followed by thiourea (Scheme 53) (67).

OEt

OEt

1. ClCOCO2Et

2. thiourea

NS O

H2N

OEt

OEt

104

Scheme 53. Synthesis of 2-iminothiazolidin-4-one.



The reaction of ethyl-, vinyl-(trichloromethyl)carbinols 105 with aqueous thiourea wasreported. Thus, 105 and alkaline thiourea gave 27–66% of the corresponding 2-imino-4-thiazolidinones 106 (Scheme 54) (68).

R

R1OH

CCl3

thiourea

R

R1

S NH

NHO

R = Et, CH=CH2, R1 = H; R = R1 = Me106105

Scheme 54. Synthesis of 2-imino-4-thiazolidinones.

Tetrachlorobenzodioxinone 107 reacted with ethanol to give ethyl 2-benzamido-2-(2,3,4,5-tetrachlorophenoxy)acetate 108 and reacted with thiourea to give N -(2-amino-4-oxo-4,5-dihydrothiazol-5-yl)benzamide 109 (Scheme 55) (69).

O

O

O

HN Ph

O

Cl

Cl

Cl

Cl

EtOH O

O

HN Ph

O

Cl

Cl

Cl

Cl

EtO

thiourea

AcOEt

N

SH2N

O

NH

O

Ph

107 108 109

Scheme 55. Synthesis of 4,5-dihydrothiazol-5-yl)benzamide.

N -(2-amino-4-oxo-4,5-dihydrothiazol-5-yl)benzamide 110 was prepared by reaction of 4-benzyl-2-phenyloxazol-5(4H)-one with chloroanil followed by thiourea (Scheme 56) (69).

N

O

Ph

O

PhN

SH2N

O

NH

O

Ph1. o-chloroanil2. EtOH

3. thiourea

110

Scheme 56. Synthesis of N -(4,5-dihydrothiazol-5-yl)benzamide.

5-(4-Hydroxybenzyl)-2,4-dioxothiazolidine derivatives, which are useful as hypoglycemic andhypolipidemic agents, were prepared. Thus 4-(2-(4-methyl-5-phenyloxazol-2-yl)ethoxy)aniline111 was reacted with methyl acrylate and thiourea to give aminothiazolidinone 112(Scheme 57) (1).

SN

O

OO

NPh

Me

NH2

NH2

OO

NPh

Me

CH

H2C CO2Me1.

2. thiourea

111112

Scheme 57. Synthesis of aminothiazolidinone.

2-Bromo-3-[4-[2-(5-ethyl-2-pyridyl)ethoxy]phenyl]propionitrile 113 was refluxed for 6 hwith thiourea and sodium acetate in ethanol to give 59% yield of 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2-imino-4-thiazolidinone 114 (Scheme 58) (70).



CN

O

NEt

Br+

S

NH2H2NNaOAc/EtOH S

HN

O

HNO N

Et113

114

Scheme 58. Synthesis of 2-imino-4-thiazolidinone.

Vinyl 2-chloroacetate underwent nucleophilic displacement with thiourea to give 2-aminothiazol-4(5H)-one 2 (Scheme 59) (71).

CH2CH

O

O

Cl

thiourea, acetone

76%

N

S

O

NH2

2

Scheme 59. Reaction of vinyl 2-chloroacetate with thiourea.

The reaction of thiourea with oxalyl chloride permits the preparation of 2-aminothiazolidin-4-one 2 (Scheme 60) (72).

OCl

OCl

thiourea, acetone

92%

N

S NH2O

O

2

Scheme 60. Reaction of thiourea with oxalyl chloride.

The synthesis of substituted 5-(2-hydroxyethyl)-2-phenylimino-1,3-thiazolidin-4-ones 115is described, starting from phenylthioureas and 3-bromotetrahydrofuran-2-one under mildconditions (Scheme 61) (73).

OO

Br

+

S

NH

H2NAr

S

HN O

NAr OH

115

Scheme 61. Synthesis of 1,3-thiazolidin-4-ones.

3. Imino-amino tautomerism

Ramsh et al. (74) reported that 2-imino-4-thiazolinone and its 2-aryl derivatives 116 exist in thecrystal state as the amino tautomers (Scheme 62).

N

S

O

NH

R

R = H, MeO, NO2, Me2N, Br

HN

S

O

N

R

116 116'

Scheme 62. Tautomerization of 2-imino-4-thiazolinone.



4. Reactions

4.1. Ring cleavage

2-Imino-4-thiazolidinone 2 was cleaved with aqueous sodium hydroxide. Treatment of the prod-uct with barium chloride, chloroacetic acid, or 1,2-dichloroethane gave barium 2-sulfidoacetate117, 2,2’-thiodiacetic acid 118, and 2,2’-(ethane-1,2-diylbis(sulfanediyl))diacetic acid 119,respectively (Scheme 63) (75).

S

NH

O

NHNaOH

BaCl2 OO Ba

S

95.2%

ClCH2CO2H SCO2H

CO2H

ClCH2CH2ClS S

CO2H CO2H

84%

96%

117

118

119

Scheme 63. Reactivity of 2 towards barium chloride, chloroacetic acid, and 1,2-dichloroethane.

2-Amino-5,5-dimethylthiazol-4(5H)-one 120 underwent ring cleavage when heated withaqueous sulfuric acid to give 2-mercapto-2-methylpropanoic acid 121 (Scheme 64) (76).

N

S

O

Me

Me

H2N H2SO4/H2O

34%CO2HMe

SH

Me

120 121

Scheme 64. Hydrolysis of 2-amino-5,5-dimethylthiazol-4(5H )-one.

4.2. Hydrolysis

2-Amino-5-ethylidenethiazol-4(5H)-ones underwent acid hydrolysis to give thiazolidin-2,4-dione which showed diverse biological activities (1, 11, 68, 77–88).

4.3. Acylation

Thiazolidinone 2 was acylated with methyl chloroformate to yield methyl 4,5-dihydro-4-oxothiazol-2-ylcarbamate 122 (Scheme 65) (89).

N

S NH2

O Cl OMe

O

NaOH/H2O

N

S NH

OO

OMe

1222

Scheme 65. Reaction of 2 with methyl chloroformate.



Acetylation of 2-aminothiazolidin-4-one 76 with acetic anhydride gave N -acetyl derivative 123(Scheme 66) (90).

N

S

O

H2N CO2H

R

Ac2O N

S

O

HN

R

CO2HMe

O

R= H, Me, Ph

76 123

Scheme 66. Acetylation of 2-aminothiazolidin-4-one.

Acetyliminothiazolidinones 125 were prepared in high yields by acetylation of 124, which existin tautomeric equilibrium with 2-amino-4-hydroxythiazolines 125 (Scheme 67) (91).

N

S

OH2N

R

Ac2ON

S

OHN

R

H3CO

HN

S

O

N

R

H3C

O

R = H, Cl, Me, MeO, NO2

124 125 125'

Scheme 67. Formation of 2-amino-4-hydroxythiazolines.

Acetylation or benzoylation of pseudothiohydantoin gave 126 and 127. The reaction of 127with the corresponding aldehyde gave 128 that had tuberculostatic activity (Scheme 68) (8, 9).

S

O

NH2

Ac2O93%

S

O

NH

O

CH3

PhCOCl90%

S

O

NH

O

Ph

R1CHO

S

O

NH

O

RR1

R = Ac, R1 = Ph, p-Me2NC6H4, p-Et2NC6H4, p-[(ClCH2CH2)2N]C6H4;R = Bz, R1 = Ph, m-O2NC6H4, p-O2NC6H4, p-Me2NC6H4, p-[(ClCH2CH2)2N]C6H4, 2-furyl

2

126127

128

Scheme 68. Acylation of pseudothiohydantoin.



4.4. Alkylation

2-Amino-5-(2-hydroxypropan-2-yl)thiazol-4(5H)-one 129 was prepared in 82% yield by alkyla-tion of 2-amino-4-thiazolidinone 2 with acetone (Scheme 69) (92).

N

S NH2

OMe2CO/Et2O

82%

N

S NH2

O

Me

Me

OH

2 129

Scheme 69. Alkylation of 2 with acetone.

Methylation of 2-aminothiazol-4(5H)-one has been reported. Treatment of 2-amino-4-thiazolidinone 2 with sodium methoxide gave 130 which underwent alkylation with methyl iodideor dimethyl sulfate to give a mixture of 131 and 132 (Scheme 70) (93).

S

NO

NH2

S

NNaO

NH

MeI or S

NO

NR

R1

S

NO

NR1

R+

MeONa

R = H, R1 = Me; R = R1 = Me

(Me)2SO4

2 130 131 132

Scheme 70. Methylation of 2-amino-4-thiazolidinone 2 .

4.5. Bromination

Bromination of 2-alkyl/arylimino-5-carbethoxythiazolidin-4-ones 49 afforded 5-bromo deriva-tives 133, which reacted with thiocarbamides to give 2-alkyl/arylimino-5-carbethoxy-5-isothiocarbamidothiazolidin-4-ones 134 and 2,7-dialkyl/arylimino-3,8-diaza-1,6-dithiaspiro[4.4]nonane-4,9-diones 135 (Scheme 71) (94).

HN

S

O

CO2Et

N

R

Br2/AcOHHN

S

O

CO2Et

N

R Br

S

NH2NH

R2 HN

S

O

CO2Et

N

R S

N

NH2

R2 HN

S

O

NR

NH

S

O

NR2+

R = H, Me, Ph, 4-MeC6H4, 4-Cl-C6H4, 2-MeO-C6H4

49 531431331

Scheme 71. Bromination of 49.

4.6. Reaction with formalin

2-Amino-5,5-bis(hydroxymethyl)-4-thiazolinone 136 was synthesized in 50% yield by treat-ing pseudothiohydantoin 2 with formalin in the presence of catalytic amount of triethylamine(Scheme 72) (95).

S

NO

OHOH

H2NN

S NH2

OHCHO/Et3N/H2O

50%

6312

Scheme 72. Formation of 2-Amino-5,5-bis(hydroxymethyl)-4-thiazolinone.



2-[(Hydroxymethyl)amino]-4-thiazolinone 137 was prepared by reaction of 2-aminothiazol-4(5H)-one 2 with formalin (Scheme 73) (96).

N

S

O

NH2HCHO/EtOH N

SO

HN OH

2 137

Scheme 73. Formation of 2-[(Hydroxymethyl)amino]-4-thiazolinone 137.

The hydroxymethylation of 2-imino-5-arylidenethiazolidin-4-ones 138 has been reported togive (E)-5-arylidene-2-(hydroxymethylamino)thiazol-4(5H)-ones 139 (Scheme 74) (97, 98).

HN

S

OHN

R HCHO N

S

O

HN

RHO

R = H, Cl, NO2, OMe, Br, F

138 139

Scheme 74. Formation of (E)-5-arylidene-2-(hydroxymethylamino)thiazol-4(5H )-ones.

4.7. Knoevenagel condensation

5-Arylidene-2-imino-4-thiazolidinone derivatives 140 were synthesized, in 10 min with 63–91%yields, by the cross-aldol condensation of aromatic aldehydes with 2-amino-4-thiazolidinone 2in sodium acetate/acetic acid under microwave irradition (Scheme 75) (99).

N

S NH2

O

+ ArCHO ACOH/AcONa

MW, 10 min, 170°C63–91%

N

S NH2

O

Ar

2 140

Scheme 75. Formation of 5-Arylidene-2-imino-4-thiazolidinone derivatives.

5-[(3,5-Dimethoxyphenyl)methylene]-2-imino-4-thiazolidinone 141 as an anti-inflammatoryagent was synthesized from 3,5-dimethoxybenzaldehyde and 2′ via Knoevenagel condensation(Scheme 76) (6).

S

NHO

NH

OMe

MeO

NH

S NH

O

+

CHO

OMeMeO

2C' 141

Scheme 76. Formation of 5-[(3,5-dimethoxyphenyl)methylene]-2-imino-4-thiazolidinone.

5-[(4-Hydroxy)-benzylidene]thiazolidine-2,4-dione 142 (an intermediate in synthesis of antidi-abetic agents) was prepared from thiourea in four steps with overall yield of 40% (Scheme 77) (2).



S

HN

O

O OH

S

H2N NH2

1. thiourea

2. 4-OH-C6H4CHO3. H3O+

40% 142

Scheme 77. Formation of 5-[(4-Hydroxy)-benzylidene]thiazolidine-2,4-dione 142 .

Treatment of 2-amino-4-thiazolidinone 2 with 2,5-dimethoxybenzaldehyde afforded thepotential cardiotonic Knoevenagel product 143 in 70% yield (Scheme 78) (7).

N

S NH2

O

CHO

OMe

OMe

+

N

S

O

H2N OMe

MeO143

2

Scheme 78. Formation of Knoevenagel product 143.

(5Z)-5-(3,5-Di-tert-butyl-4-hydroxybenzylidene)-2-aminothiazol-4(5H)-one 144 was pre-pared by Knoevenagel condensation of 2-amino-4-thiazolidinone 2 with 2,6-di-tert-butyl-4-formylphenol (Scheme 79) (100).

N

S NH2

OOHC

OH

Bu-t

Bu-t

+AcOH/AcONa

reflux, 19 h38%

N

S

NH2

O

OH

Bu-t

Bu-t

2

144

Scheme 79. Reaction of 2 with 2,6-di-tert-butyl-4-formylphenol.

Quinazolin-4(3)-ones bearing different 2-amino-4-thiazolidinone as potential antiinflammatoryagent were reported. Thus the Knoevenagel condensation of 2-amino-4-thiazolidinone 2 with3,4-dihydro-4-oxo-3-phenylquinoline-2-carbaldehyde led to (Z)-2-amino-5-((4-oxo-3-phenyl-3,4-dihydroquinolin-2-yl)methylene)thiazol-4(5H)-one 145 (Scheme 80) (101).

N CHO

O

Ph

N

S NH2

O

+EtOH/AcONa

57%

N

O

Ph

NS

NH2

O

2 145

Scheme 80. Reaction of 2 with 3,4-dihydro-4-oxo-3-phenylquinoline-2-carbaldehyde.



Chowdhry et al. (102) reported the synthesis of bidentate ligand (Z)-2-amino-5-(pyridin-2-ylmethylene)thiazol-4(5H)-one 146 by condensation of 2-aminothiazol-4(5H)-one 2 withpicolinaldehyde (Scheme 81).

N

S NH2

ON

CHO

+1) Na2CO3, glycine

2) H2O90%

N

SNH2

O

N

2146

Scheme 81. Reaction of 2 with picolinaldehyde.

The arylidene derivatives 147 were also prepared through reaction of 2 with aromatic alde-hydes. 147 Reacted with hydrazine hydrate and urea to give thiazolodihydropyrazole 148 andthiazolotetrahydropyrimidone 149, respectively (Scheme 82) (102).

N

S NH2

O

+N

S

H2N

O

N2H4/EtOH

68%

N

SH2N

NHHNCHO

OMe

OMe

MeO

OMe

OMe

OMe

OMe

OMe

OMe

H2N NH2

O

EtOH/Na78%

HN

NH

N

S

O

NH2

OMe

OMeMeO

R = Ph, 4-ClC6H4, 3,4,5-(MeO)3C6H2

2 147148

149

Scheme 82. Formation of thiazolodihydropyrazole and thiazolotetrahydropyrimidone.

Substituted 1,5-naphthyridine thiazolinones 151 reported to have antiproliferative and anti-cancer activities. 6-Formyl-4-isopropoxy-1,5-naphthyridine-3-carbonitrile 150 was condensedwith 2-amino-4-thiazolidinone 2 to afford the Knoevenagel product 151 in 23% yield(Scheme 83) (5).

N

N

O

NC CHO N

S NH2

O

+AcONa/AcOH

23%

N

N

O

NC

N

S NH2

O

150 2 151

Scheme 83. Formation of 1,5-naphthyridine thiazolinones.

(Z)-5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-methylene]-2-imino-4-thiazolidinone153 is useful as dual 5-lipoxygenase and cyclooxygenase inhibitors with antiinflammatoryactivity, and was prepared in 38% yield by reaction of 2-imino-4-thiazolidinone 2 with3,5-di-tert-butyl-4-hydroxybenzaldehyde 152 (Scheme 84) (10).



S

HN

O

HN

OH(H3C)3C

C(CH3)3

CHO

OH

(H3C)3C C(CH3)3

+S

HN

O

HN

AcOH/AcOH

ref lux, 48 h38%

152 2 153

Scheme 84. Reaction of 2 with 3,5-di-tert-butyl-4-hydroxybenzaldehyde.

Quinolinyl-methylene-thiazolinones have been reported as potent and selective cyclin-dependent kinase 1 (CDK1) inhibitors. Thus, the Knoevenagel condensation of 2-amino-4-thiazolidinone 2 with quinoline-6-carbaldehyde derivatives 154 led (Z)-2-amino-5-((2,4-dialkylquinolin-6-yl)methylene)thiazol-4(5H)-one 155 (Scheme 85) (103, 104).

N

SNH2

O N

OHC

+AcONa/AcOH

130°C, 12h

NS

NH2

O

N

R2

R1

R1

R2

R1=R2 = H; R1 =NHAc, R2= OEt

2154

155

Scheme 85. Reaction of 2 with quinoline-6-carbaldehyde derivatives.

Quinazolinylmethylene thiazolinones as CDK1 inhibitors were prepared. Thus, the Kno-evenagel condensation of 2-amino-4-thiazolidinone 2 with 4-ethoxyquinazolin-6-carbaldehyde156 afforded stereo-selectively, (5Z)-2-amino-5-((4-ethoxyquinazolin-6-yl)methylene)thiazol-4(5H)-one 157 (Scheme 86) (105).

N

SNH2

O

N

N

OHC

OEt

+ NS

H2N

O

N

N

OEt

AcOH/AcOH

ref lux, 12h

2156

157

Scheme 86. Reaction of 2 with 4-ethoxyquinazoline-6-carbaldehyde.

Stereoselective synthesis of ethyl 3-[(9E)-(2-amino-4-oxothiazol-5(4H)-ylidene)methyl]-1H -indole-2-carboxylate 159 was achieved in 67% yield by condensation of ethyl 3-formyl-1H -indole-2-carboxylate 158 with 2-amino-4-thiazolidinone 2 under Knoevenagel conditions(Scheme 87) (106).

N

S NH2

OHN

CHO

CO2Et+

AcOH/AcONa

ref lux, 8.5 h67%

HN

CO2EtN

S NH2

O

2 158 159

Scheme 87. Reaction of ethyl 3-formyl-1H -indole-2-carboxylate.



Thiazolone-based sulfonamides were prepared as inhibitors of nonstructural protein5B polymerase. Thus, 4-methylbenzene-1-sulfonyl chloride was condensed with 2-amino-4-thiazolidinone 2 to afford sulfonamide 160, that condensed with (E)-3-(pyridin-2-yl)acrylaldehyde under the Knoevenagel condition to give compound 161 (Scheme 88) (14).

N

SNH2

O

S OO

Cl

Me

+Et3N/THF

80°C, 1h

N

S

HN

O S

O

OMe

N H

HCHO

NS

HN

O

S

O

O

MeN

H

H

H

2 160

161

Scheme 88. Reaction of 2 with 4-methylbenzene-1-sulfonyl chloride.

(5E)-5-((1H -Pyrrolo[2,3-b]pyridin-3-yl)methylene)-2-aminothiazol-4(5H)-one 163 was pre-pared in 82% yield as anti-cancer agent by the Knoevenagel condensation of 2-amino-4-thiazolidinone 2 with 1H -pyrrolo[2,3-b]pyridine-3-carbaldehyde 162 (Scheme 89) (3).

N

S NH2

ON

HN

CHO

+AcONa/AcOH

reflux, 12h82%

N HN

N

SNH2

O

2 361261

Scheme 89. Reaction of 2 with 1H -pyrrolo[2,3-b]pyridine-3-carbaldehyde.

Heterocyclic arylidene aryl ether compounds are useful for treating diseases or disorders medi-ated through modulation of estrogen-related alpha receptors. The Knoevenagel condensation of 2-amino-4-thiazolidinone 2 with 4-(4-(trifluoromethyl)-2-nitrophenoxy)-3-methoxybenzaldehyde164 afforded (5Z)-5-(4-(4-(trifluoromethyl)-2-nitrophenoxy)-3-methoxybenzylidene)-2-amino-thiazol-4(5H)-one 165 (Scheme 90) (107).

N

S NH2

O

+

O

OMe

NO2

OHC CF3

EtOH/NH4OAc

ref lux, 24h98%

N

S NH2

O

O

MeO

NO2

F3C

2 164165

Scheme 90. Reaction of 2 with 4-(4-(trifluoromethyl)-2-nitrophenoxy)-3-methoxybenzaldehyde.

Thiazolinone 3,4-disubstituted quinolines as CDK1 inhibitors for treating cancer was reported.6-((15E)-(2-Amino-4-oxothiazol-5(4H)-ylidene)methyl)-4-ethoxyquinoline-3-carbonitrile 167was prepared by reaction of 2-amino-4-thiazolidinone 2 with 4-ethoxy-6-formylquinoline-3-carbonitrile 166 (Scheme 91) (4).



N

S NH2

O

+

N

CN

OEt

OHC

AcOH/AcONa

110°C, 4h47%

NCN

OEtN

SH2N

O

2 166 167

Scheme 91. Reaction of 2 with 4-ethoxy-6-formylquinoline-3-carbonitrile.

The Knoevenagel condensation between 4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzaldehyde168 and pseudothiohydantoin 2 afforded (Z)-5-(4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)benzy-lidene)-2-aminothiazol-4(5H)-one 169 in 94% yield as potent and selective human β3 agonists(Scheme 92) (108, 109).

OHCO

ON

N

S NH2

O

+EtOH/piperidine

94%

NS

H2N

OCHO

ON

8612 169

Scheme 92. Reaction of 2 with 4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzaldehyde.

Synthesis and in vitro activity of rhodanine-based phosphodiesterase-4 (PDE4) inhibitorshas been described. Knoevenagel condensation of 2-imino-4-thiazolidinone 2 with 3-(cyclopentyloxy)-4-methoxybenzaldehyde 170 in sodium acetate/acetic acid under reflux-ing conditions for 4 h afforded 5-(3-(cyclopentyloxy)-4-methoxybenzylidene)-2-aminothiazol-4(5H)-one 171 (Scheme 93) (110).

O

OMe

OHC N

S

O

NH2

+AcOH/AcONa

reflux, 4h

NSO

NH2

O

MeO2170 171

Scheme 93. Reaction of 2 with 3-(cyclopentyloxy)-4-methoxybenzaldehyde.

Condensation of isatin derivatives 172 with 2-aminothiazol-4(5H)-one 2 in refluxing ethanolafforded isatylidene derivatives 173 in good yields, and showed promising antibacterial activity(Scheme 94) (111, 112).

NH

O

OR1

R2

+N

S NH2

OEtOH

NH

O

R1

R2

N

S

NH2

O

R1=R2=H, Me; R1= H, R2=Me

2172 173

Scheme 94. Reaction of 2 with isatin derivatives.

A facile synthesis of thiazolidinone 175 was described by the Knoevenagel-type condensation ofbenzo[b]thiophene-2,3-dione 174 (commonly known as thioisatin) with 2-amino-4-thiazolidinone2 (Scheme 95) (113).



N

S NH2

OS

O

O+EtOH, reflux, 8h

72%

N

SNH2

OS

O

2 174 175

Scheme 95. Condensation of 2 with benzo[b]thiophene-2,3-dione.

The synthesis of acenaphthylidene derivative 177 involved the Knoevenagel-type condensationof 2-amino-thiazolidin-4-one 2 with acenaphthylene-1,2-dione 176 (Scheme 96) (114).

OO

N

S

O

NH2

+EtOH

reflux, 6 h87%

O

N

S

O

NH2

176177

Scheme 96. Condensation of 2 with acenaphthylene-1,2-dione.

Condensation of 2-imino-4-thiazolidinone 2 with 1,4-cyclohexanedione gave 5,5′-(1,4-cyclohexanediylidene)bis[2-imino-4-thiazolidinone] 178 (Scheme 97) (112).

HN

S

O

NH

O O

EtOH, reflux, 2 h45%

NH

S

O

NH

HN

S

O

HN

2' 178

Scheme 97. Condensation of 2 with 1,4-cyclohexanedione.

(E)-ethyl 5-amino-2-benzylidene-3-oxo-7-phenyl-3,7-dihydro-2H -thiazolo[3,2-a]pyrimi-dine-6-carboxylate 181 was obtained by reaction of (5Z)-2-amino-5-benzylidenethiazol-4(5H)-one 179 with ethyl 2-cyano-3-phenylacrylate 180 (Scheme 98) (115).

N

S

O

Ph

H2N +HC

CNEtO2C

PhEtOH/Et3N

N

N

NH2

EtO2C

Ph S

O

Ph

179 180181

Scheme 98. Formation of thiazolo[3,2-a]pyrimidine derivatives.

(E)-2-benzylidene-3,5-dioxo-7-phenyl-3,5-dihydro-2H -thiazolo[3,2-a]pyrimidine-6-carbon-itrile 183 was prepared by reaction of ethyl 2-cyano-3-oxo-3-phenylpropanoate 182 with2-amino-5-benzylidenethiazol-4(5H)-one 179 in a mixture of acetic and hydrochloric acid(Scheme 99) (116).

N

SH2N

O

Ph+ CN

CO2Et

O

Ph HCl/AcOH

60%N

N S

O

Ph

O

Ph

NC

179 182 183

Scheme 99. Reaction between 179 and ethyl 2-cyano-3-oxo-3-phenylpropanoate.



4.8. Mannich reactions

The Mannich reaction of aminothiazolidinone 2 with aqueous formaldehyde and diphenylaminegave 44% 2-((diphenylamino)methylamino)thiazol-4(5H)-one 184 (Scheme 100) (117).

N

S NH2

OHCHO/Ph2NH

44%

N

S NH

O

NPh

Ph

2 184

Scheme 100. Formation of 2-((diphenylamino)methylamino)thiazol-4(5H)-one.

The aminomethylation of 2-iminothiazolidin-4-ones by aqueous formaldehyde and pri-mary amines was studied. Thiazolotriazines 186 were prepared in 68–91% yields by theaminomethylation of iminothiazolidinones 185 with primary amines and aqueous formaldehyde(Scheme 101) (118).

N

S

O

H2NR1

R2

RNH2/CH2O

68–91%

N

S

O

N R1

R2

N

R

R = Ph, 2-naphthyl; R1=H, R2=Et, Ph

185 186

Scheme 101. Formation of thiazolotriazines.

Similarly, iminothiazolidinone 2 gave 22 and 28% thiazolotriazines 187 with t-butylamine andbenzylamine (Scheme 102) (118).

HN

SHN

ORNH2/CH2O

22-28%

N

SN

O

CH2OHN

R

R = Me3C, PhCH2

2' 187

Scheme 102. Mannich reaction with t-butylamine and benzylamine.

Thiazolotriazinones 189 were prepared in 42–90% yields by Mannich reactions of 188 withformaldehyde and primary amines (Scheme 103) (119).

R1 = R2 = H, R3 = Me, Ph, m-, p-tolyl, p-MeOC6H4, m-ClC6H4, m-BrC6H4, m-O2NC6H4, 2-C10H7;R1 = H, R2 = Me,R3 = 2-C10H7; R1R2 = PhCH, p-ClC6H4CH, p-FC6H4CH, p-BrC6H4CH, R3 = Me; R1R2 = PhCH, R3 = Ph

HN

S

O

HN

R1

R2

R3NH2, HCHO N

S

O

N

R1

R2

NR3

188 189

Scheme 103. Formation of thiazolotriazinones.

Additionally (Z)-3-((2-iodophenylamino)methyl)-2-((2-iodophenylamino)methylaimino)thiazolidin-4-one 190 was obtained in 32% yield through the aminomethylation of 2 with2-iodoaniline (Scheme 104) (118).



N

SH2N

O

CH2O

32%

NH2

I

+

NS

N

O

NH HN

I I2190

Scheme 104. Mannich reaction with 2-iodoaniline.

The aminomethylation of arylidene 2-aminothiazolidin-4-ones 138 by aqueous formaldehydeand aniline afforded thiazolotriazines 191 (Scheme 105) (118).

N

S

O

H2N

R

HCHO, PhNH2

76–90%

NS

O

NRNPh

R=Br, Cl138

191

Scheme 105. Synthesis of thiazolotriazines.

The aminomethylation of 2-imino-5-arylidenethiazolidin-4-ones 138 have been reported togive (E)-5-benzylidene-2-(piperidin-1-ylmethylamino)thiazol-4(5H)-ones 192 (Scheme 106)(96, 97).

HN

S

OHN

RHCHO, piperidine N

S

O

HNRN

R = H, Cl, NO2, OMe, Br, F

138 192

Scheme 106. Aminomethylation of 2-imino-5-arylidenethiazolidin-4-ones.

4.9. Reaction with phenylisocyanate derivatives

Thiazolidone 2 reacted with phenylisothiocyanate to give 2-imino-5-phenylaminothiocar-boxamido-4-thiazolidone 193 which was converted to a thiazolopyrazole 194, a thiazolopyridine195, and a (phenylamino)thiazoleamine 196 by reaction with hydrazine hydrate, malononitrile,and aniline (Scheme 107) (120).

N

S NH2

OPhNCS, EtOH

30%

N

S NH2

O

S

PhHN N2H4/EtOH

40%

N

S

NN

H2N NHPh

CH2(CN)2, Et3N, EtOH

60%

N S

NNH2

S

Ph

CN

H2NPhNH2 / EtOH

56%

N

SH2N

S

NHPh

NHPh

2 193194

195196

Scheme 107. Reaction of 2 with phenylisothiocyanate.



2-Amino-4-thiazolidinone 2 was reacted with benzoyl isothiocyanate in refluxing acetoni-trile to give N -(4-oxo-4,5-dihydrothiazol-2-ylcarbamothioyl)benzamide 197 with 55% yield(Scheme 108) (121).

N

S NH2

OO

NCSPh +MeCN, reflux, 3h

55%

N

S NH

O S

NH

O

Ph

2 197

Scheme 108. Reaction of 2 with benzoyl isothiocyanate.

2-Aminothiazolidinone 198 reacted with benzoyl isocyanate and sulfurisocyanatidic chlorideto give thiazolyl ureas 199 and thioureas 200, respectively (Scheme 109) (122).

N

S

O

R1H2N

O

Ph NCO

toluene

N

S

O

R1

NH

O

NH

O

Ph

R2

R2

ClSO2

NCO

THF/H2O

N

S

O

R1

NH

R2

O

H2N

R1=H, R2 = Me; R1= H, R2= CO2Et; R1= Me, R2= CO2Et

198199200

Scheme 109. Formation of thiazolyl ureas and thioureas.

4.10. Reaction with hydrazines

The reaction of 49 with hydrazines afforded 2-arylimino-2,3,4,5-tetrahydropyrazolo[3,4-d]-thiazol-6(H)-ones 201. Bromination of 49 afforded 5-bromo derivatives 202, which upon reactionwith thiocarbamides gave 2-alkyl/arylimino-5-carbethoxy-5-isothiocarbamidothiazolidin-4-ones203 and 2,7-dialkyl/arylimino-3,8-diaza-1,6-dithiaspiro[4.4]nonane-4,9-diones 204 (Scheme 110)(38).

HN

S

O

CO2Et

NR

R1NHNH2

HN

S

R1N

NR

O

NH

Br2/AcOHHN

S

O

CO2Et

NR Br

S

NH2NH

R2 HN

S

O

CO2Et

NR S

N

NH2

R2

HN

S

O

NR

NH

S

O

NR2+

R = H, Me, Ph, 4-MeC6H4, 4-ClC6H4, 2-MeOC6H4

49201

202 203 204

Scheme 110. Reaction with hydrazines and bromine.

Pyrazolinothiazolidin-2-ones 206 were prepared from rhodamine benzylidene derivatives205 by condensation with phenylhydrazines, some of them showed antifungal activity(Scheme 111) (123).

4.11. Formation of enaminones

The enaminones of 2-aminothiazol-4(5H)-ones 207 and 208 were prepared by reac-tion of 2 with methoxy-N ,N ,N ′,N ′-tetramethylmethanediamine or t-butoxy-N ,N ,N ′,N ′-tetramethylmethanediamine in aceteonitrile. Thiooxoaplysinopsin derivative 209 was prepared



N

S

O

RH2N

+ R1NHNH2

AcONa/AcOH

NH

S

N

R

O N R1

R = Ph, 4-ClC6H4, 4-MeOC6H4, 4-O2NC6H4; R1 = Ph, 4-O2NC6H4

205 206

Scheme 111. Formation of Pyrazolinothiazolidin-2-ones.

by reaction of N -substituted thiohydantoin 208, Bredereck’s reagent, and 2-methylindole(Scheme 112) (124, 125).

N

S NH2

O

NMe2

OBu-tMe2N

N

S NMe2

O

NMe2

MeCN

NMe2

OMeMe2N

MeCN

N

S N

O

Me2N

NMe2

HN

H3C

HBr/AcOH

N

S NMe2

O

NH

CH3

2

207208

209

Scheme 112. Formation of enaminones.

4.12. Different reactions

Ketoketene thioacetals, which were formed by treatment of 2-amino-1-propene-1,1,3-tricarbonitrile 210 with carbondisulphide or with phenylisothiocyanate, were allowed toreact with 2-aminothiazol-4(5H)-one 2 under phase transfer catalytic (PTC) conditions toafford thiopyrano[2,3-b]pyridine or pyrido[2,3-b]pyridine derivatives 211 and 212, respectively(Scheme 113) (126).

CN

CN

H2N

NC

N

S NH2

O

+CS2, Bu4NBrK2CO3, dioxane75%

S

N

S

CN

H2N NH2

S

H2N

PhNCS,Bu4NBrK2CO3, dioxane73%

N

N

S

CN

H2N NH2

S

H2N

Ph

2209

210211

Scheme 113. Synthesis of pyrido[2,3-b]pyridine.



Thiazolo[3,2-a]pyrimidine 212 was prepared in one-pot reaction from 2-imino-4-thiazolidinone 2 and malononitrile (Scheme 114) (116).

N

SNH2

O

+CN

CN

EtOH/Et3N N

N

O

S

NH2

HN

2 212

Scheme 114. Reaction of 2 with malononitrile.

Dispiro[thiazolidine-2,2′-[1,3]diazetidine-4′,2"-thiazolidine]-5,5"-diacetic acid 213 was pre-pared in 60% yield by reaction of 3,4-dichlorocinnamic acid with pseudothiohydantoin 2(Scheme 115) (127).

O

CO2H

Cl

Cl

S

NH

HN

NH

S

HNO

O CO2H

CO2HO

OCl

ClCl

Cl

+N

S NH2

Otoluene

60%

2

213

Scheme 115. Formation of dispiro compound.

The reaction of 2-amino-4-oxothiazolidine-5-acetic acid 214 with p-aminostyrene in thepresence of dicyclohexylcarbodiimide (DCC) gave a new monomer 215 which was obtainedconveniently under mild conditions (Scheme 116) (77).

N

S

O

H2NCO2H

+

NH2

HCCH2

DCC N

SH2N

OO

NH

HC

CH2

214 215

Scheme 116. Reaction with p-aminostyrene.

Thiazolidineacetic acids 216 which was amidated by first making the acid chloride thenamination by morpholine, piperidine, aniline, phenylhydrazine, or prop-2-en-1-amine gave thecorresponding amides 217 and 218, respectively (Scheme 117) (128, 129).



N

S

O

HO2C

N

R = H, Ph, allyl, R1 = H; R = Ph, R1 = Et, Bu, cyclohexyl, Ph;R = R1 = Me2CH, cyclohexyl; R = PhCH2, R1 = MeQ = Ph, PhNH, or CH2:CHCH2; X = CH, O

R1

R

1. SOCl2

2. QNH2

N

S

O

N

R1

R

O NHQX

NH

N

S

O

N

R1

R ON X

216

217

2181. SOCl2 2.

Scheme 117. Formation of amides.

Thiophosphorylation of thiazolidinone was achieved. Thiazolidine 220 was prepared in 25%yield by condensing 2 with o-phenyl methylphosphonochloridothioate 219 (Scheme 118) (126).

S

P MeO

ClPh +

N

SNH2

OEt3N/pyridine

25%

N

S

HN

O PS

MeOPh

219 220

Scheme 118. Synthesis of thiazolidine.

Acknowledgements

The authors would like to thank the faculty of Science & Arts in Khulais, King Abdel-Aziz University, KSA for valuablesupport.

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