application of guanidine and its salts in multicomponent reactions · guanidine, also called...

Turk J Chem

(2014) 38: 345 – 371

c⃝ TÜBİTAKdoi:10.3906/kim-1307-38

Turkish Journal of Chemistry

http :// journa l s . tub i tak .gov . t r/chem/

Research Article

Application of guanidine and its salts in multicomponent reactions

Mahshid RAHIMIFARD, Ghodsi MOHAMMADI ZIARANI∗, Boshra MALEKZADEH LASHKARIANIDepartment of Chemistry, Alzahra University, Tehran, Iran

Received: 15.07.2013 • Accepted: 21.11.2013 • Published Online: 14.04.2014 • Printed: 12.05.2014

Abstract:This review gives an overview of the application of guanidine and its salts in multicomponent reactions. It can

act as a catalyst or solvent for multicomponent reactions or as a reagent for synthesis of substituted diazines, triazines,

and macroheterocycles by multicomponent reactions.

Key words: Guanidine, guanidinium salt, multicomponent reaction, pyrimidine, pyrimidinone, triazine

1. Introduction

Guanidine, also called carbamidine, is a strongly alkaline and water-soluble compound that plays a key role in

numerous biological activities. The guanidine group defines chemical and physicochemical properties of many

compounds of medical interest.1 Trimethoprim2 1, sulfadiazine3 2, and Gleevec (imatinib mesilate)4 3 are

examples of pharmaceutically important guanidine-containing heterocycles (Figure). In peptides, residue of

arginine has a guanidine structure in the protonated form as guanidinium ion, which functions as an efficient

identification moiety of anionic substrates such as carboxylate, nitronate, and phosphate functionalities.5 The

guanidinium ion is also involved in many enzymatic transformations, because it can orient specific substrates

based on their electronic characteristic and it is able to form a transition state assembly with the substrates to

reduce the activation energy or to stabilize anionic intermediates.6

MeO

MeO

OMe

N

N

NH2

NH2

H2N

S

HN

OO N

N

N

N N

HN

Me

HN

O

N

N

Me

1 2 3

Figure. Typical compounds containing a guanidine substructure.

Multicomponent reactions are of increasing importance in organic and medicinal chemistry because this

kind of reaction provides a powerful tool for the 1-pot synthesis of small heterocycles and complex compounds.7,8

∗Correspondence: [email protected]

345

RAHIMIFARD et al./Turk J Chem

Using guanidine and its salt as reagent in multicomponent reactions usually leads to the formation of guanidine-

containing heterocycles, which are a very important class of therapeutic agents, and they are suitable for the

treatment of a wide spectrum of diseases.1,9−11 Guanidinium salts are also environmentally friendly catalysts

for some multicomponent reactions.12,13 This review covers the application of guanidine and its salts from these

points of view.

2. Guanidine as a reagent

2.1. Synthesis of 2-aminopyrimidine compounds

2.1.1. Synthesis of 4,6-diaryl compounds

One-pot synthesis of 2-amino-4,6-diarylpyrimidine 7 by multicomponent reaction of aromatic aldehydes 4,

acetophenones 5, and guanidinium carbonate 6 in the presence of sodium hydroxide under solvent-free conditions

was reported by Zhuang et al. (Scheme 1).14

CO32-

6

H2N NH2

NH2

2

70 °C, 25 min

O

H

R1

O

Me

R2 N

N

7

NH2

R2

R1

4 5

R1 = H, 4-Me, 4-F, 4-Cl,

4-Br, 2-Cl, 2,4-Cl2, 4-MeO

R2 = H, 4-Cl, 4-MeO

+ +

88-96%

NaOH

Scheme 1

4,6-Diaryl amino pyrimidines 7 were also synthesized by 3-component condensation of aromatic alde-

hydes 4, acetophenones 5, and guanidinium chloride 8 in PEG-400 in the presence of KOH. A series of

new dioxothiazolidin-5-yl)-N-(4,6-diphenylpyrimidin-2-yl) acetamides 10 has been prepared by condensing 2,4-

thiazolidinedione acetic acid 9 with diaryl amino pyrimidines 7 in DMF using N,N-dicyclohexylcarbodimide

(DCC) at room temperature (Scheme 2).15

Pyridylpyrimidine is a N,N’-chelating ligand that has 4 N-donors and can act as a neutral mono- or

bidentate ligand and an anionic tridentate ligand. An easy and highly efficient 1-pot reaction for the preparation

of 4-aryl-6-(pyridin-2-yl)pyrimidin-2-amine 12 via the reaction of different aromatic aldehydes 4, acetylpyridine

11, and guanidinium carbonate 6 in the presence of NaOH under solvent-free conditions was reported by Tao

et al. (Scheme 3).16

Rong et al. reported a mild protocol for the synthesis of 4-naphthylpyrimidin-2-amine derivatives 14 (or

16) by the reaction of aromatic aldehydes 4 (or 1-naphthaldehyde 15), 2-acetylnaphthalene 13 (or acetophenones

5) with guanidinium carbonate 6 in the presence of sodium hydroxide under solvent-free conditions (Schemes

4 and 5).17

346


Cl

8

H2N NH2

NH2

r.t., 10 h

O

H

R1

O

Me

R2 N

N

7

NH2

R2

R1

4 5

R1 = 4-Me, 4-MeO,4-F, 2-Cl, 4-Cl, 4-Br

R2 = H, 4-OH, 4-MeO

+ +

82-89%

Aq. PEG-400, KOH

DCC, DMFr.t. 7 h

S

HNO

HO

O

O

9

N

N

10

NH

R2

R1O S

NH

O

O

71-78%

Scheme 2

CO32-

6

H2N NH2

NH2

2

O

H

R

N

O

Me

N

N

12

NH2N

R

4 11

R = 2-F, 3-F, 4-F, 4-Cl, 2,4-Cl2, 3,4-Cl2, 2-Br, 4-Br, 4-Me,

3,4-Me2, 3-MeO, 4-MeO, 3,4-(MeO)2, 3,4,5-(MeO)3

70 °C, 45 min

NaOH++

89-96%

Scheme 3

Eynde et al. described the synthesis of ethyl 2-amino-4-aryl-1,4-dihydro-6-phenylpyrimidine-5-carboxylates

18 from 1-pot cyclocondensation of arylaldehydes 4, ethyl benzoylacetate 17, and guanidinium chloride 8. This

amino-dihydropyrimidines can readily react under microwave irradiation and solvent-free conditions, with 3-

formylchromone 19 or diethyl(ethoxymethylene)malonate 20 to yield novel pyrimido[1,2-a ]pyrimidines 21 or

22, respectively (Scheme 6).18

347


CO32-

6

H2N NH2

NH2

2

O

Me

N

N

14

NH24 13

R = 4-Me, 4-MeO, 3,4-(MeO)2, 4-F, 4-Br, 4-Cl, 2,4-Cl2, 3,4-Cl2

NaOH

70 °C, 30 min

H

O

R

R

++

81-91%

Scheme 4

CO32-

6

H2N NH2

NH2

2

O

Me

RN

N

16

NH2

R15 5

R = H, 4-Me, 4-MeO, 2,4-Me2, 3-Cl, 2,4-Cl2

O H

NaOH

70 °C, 30 min+ +

81-91%

Scheme 5

H2N NH2

NH2

Ar

O

H

O

4

Ar = Ph, 4-MePh, 4-MeOPh, 4-ClPh, 2-thienyl

+

CO2Et

+

NH

N

NH2Ph

EtO2C

HArN

N

N

O

OHHAr

EtO2C

Ph

NaHCO3/DMF

Cl

OO

O

H

70 °C, 3 h

EtO H

CO2EtEtO2CN

N

NH

HAr

EtO2C

Ph H

O

CO2Et

75-85%

17 8 18

19

20

21

22

Scheme 6

2.1.2. Synthesis of pyrimidine-fused ring systems

Spring et al. used a branching synthetic strategy to generate structurally diverse scaffolds such as pyrimido[1,2-

a ]pyrimidine that developed numerous biologically active compounds. Reaction of β -keto-ester 23, thiophene-

348


2-carboxaldehyde 24, and guanidinium carbonate 6 followed by reaction with 3-formylchromone 19 led to the

formation of pyrimido[1,2-a ]pyrimidine 25 (Scheme 7).19

N

N

N

S

O

Ph

O

OC6F13

OH

O

OC6F13

OPh

CO32-

6

H2N NH2

NH2

2

S

CHO

23 24

19

25

+ +

43%

OO

H

O

Scheme 7

The heterocyclic pyrido[2,3-d ]pyrimidines ring system represents several biological activities. Some ana-

logues have been found to act as antitumor agents inhibiting dihydrofolate reductases or tyrosine kinases,20−22

while others are known antiviral agents.23 A simple and rapid multicomponent reaction providing multifunc-

tionalized pyrido[2,3-d ]pyrimidines 29 in a microwave-assisted 1-pot cyclocondensation of α ,β -unsaturated

esters 26, malononitrile 27, or methyl cyanoacetate 28 and guanidinium carbonate 6 was reported by Borrell

et al. (Scheme 8).24,25

CO32-

6

H2N NH2

NH2

2 N

N

29

NH2

26 27, X = CN28, X = CO2Me

R1 = H, Me

R2 = H, Me, Ph

MW, 140 °C, 10 min

NaOMe/MeOH

NH

O

R1

R2 Y

X

CN

R2

R1 CO2Me

X = CN, Y = NH2X = CO2Me, Y = OH

+ +

Scheme 8

Use of guanidinium carbonate in the synthesis of pyrido[2,3-d ]pyrimidines was previously described by

Borrell et al. in 2 manners. In the first method, pyrido[2,3-d ]pyrimidines were synthesized by treatment

of isolated pyridones with guanidinium carbonate,26,27 and the second method based on the reaction of

guanidinium carbonate with isolated Michael adduct of acrylate and cyano-compounds.28−30

Galve et al. have developed a protocol for the synthesis of 2-arylamino substituted 4-amino-5,6-

dihydropyrido[2,3-d ]pyrimidin-7(8H)-ones 33 from treatment of pyridones 30 (synthesized from α ,β -unsaturated

esters 26 and malononitrile 27) with the aryl guanidines 31 to form 3-aryl substituted pyridopyrimidines 32,

which underwent Dimroth rearrangement by NaOMe/MeOH. The overall yields of such a 3-step protocol are in

general higher than those of the multicomponent reaction between an α ,β -unsaturated ester 26, malononitrile

27, and an aryl guanidine 31 (Scheme 9).31

349


H2N NHR3

NH

N

N

NH2

R1 = H, Me, 2,6-Cl2PhR2 = H, Me

R3 = Ph, 4-ClPh

NaOMe/MeOH

NH

O

R1

R2 NH

CN

CN

R2

R1 CO2Me

R3

1,4-dioxaneNH

O

R1

R2

OMe

CN

NaOMe/MeOH

H2N NHR3

NH

N

N

NHR3NH

O

R1

R2 NH226

27 30

31

32

33

31

MW, 140 °C10 min

Scheme 9

Jin et al. reported glycosylation of the pyrido[2,3-d ]pyrimidine ring in the synthesis of the guanosine

analogue system. Pyrido[2,3-d ]pyrimidine ring system 35 has been synthesized by condensation of methyl

acrylate 34 with methyl cyanoacetate 28 and guanidinium carbonate 6 in the presence of sodium methoxide.

Dehydrogenation, glycosylation, and deprotection of pyrido[2,3-d ]pyrimidine ring gave the desired guanosine

analogue 36 (Scheme 10).32

CO32-

6

H2N NH2

NH2

2N

NH

35

NH2

34

Reflux, 36 h

NaOMe/MeOH

NH

OCO2Me

CNCO2Me

28

O

N

NH

NH2NO

O

O

HO OH

OH

36

+ +

55%

Scheme 10

An environmentally friendly method for the synthesis of pyrimidine-fused ring systems 39 or 40 by the

1-pot condensation of aromatic aldehydes 4, guanidinium carbonate 6, and cyclic ketones 37 or 38, respectively,

in the presence of NaOH under solvent-free conditions was reported by Rong et al. (Scheme 11).33

2-Amino-4-benzylaminoindeno[2,1-d ]pyrimidin-5-one 43 was synthesized by condensation of α -oxoketene

dithioacetal 41,34 aniline 42, and guanidinium carbonate 6 by Tominaga et al. (Scheme 12).35

350


CO32-

6

H2N NH2

NH2

2

O

H

R

N

N

39

NH2

4

R = H, 4-Me, 4-MeO, 3,4-Me2, 3,4-

(MeO)2, 4-Br, 4-Cl, 3-Cl, 3,4-Cl2, 4-F

O

n = 0,1

NaOH, 70 °C,15 min

O

n = 0,1

NaOH, 70 °C,15 min

R

N

N

40

NH2

R

R

n

n

37

38

+

90-98%

90-97%

Scheme 11

N

N

NH2

MeS

MeS HN

CO32-

H2N NH2

NH2

2

NH2O

O

OPyridine

Reflux

41 42 6 43

+ +

92%

Scheme 12

The synthesis of 4-phenyl-5H -pyrimido[5,4-b ]indol-2-amine 45 via a multicomponent reaction between

1-acetylindolin-3-one 44, benzaldehyde 4, and guanidinium chloride 8 (Scheme 13) and its antagonist activity

of A2A adenosine receptor were studied by Matasi et al.36

H2N NH2

NH2+ +

NaOHH

O

N

O

MeO

Cl

N

N

NH2

HN

EtOH

44

4 8

45

Scheme 13

351


Meshram et al. synthesized new spiro[indenopyrimidine] derivatives 51 and 52, and spiro[pyrimidodiazine]

derivatives 53 and 54 by a simple 1-pot 3-component reaction involving cyclic ketones 49 and 50, guanidine

46, and 1,3-dione 47 and 48 in the presence of HCl (10% mmol) in ethanol at reflux (Scheme 14).37

H2N NH2

NH

N

NH

NH2

O

HN

O

NH

O

O

O

O

O

N

NH

NH2

OO

O

O

O

N

NH

NH2

O

O

3 h, 75%

5 h, 84%

HN NH

O

O O

NHHN

O

O

N

NH

NH2HN

O

NHHN

O

O

NH

O

O

O

O

O

3 h, 78%

3 h, 82%

HCl/EtOH HCl/EtOH

Reflux Reflux

49 49

5050

4847

46

51

52

53

54

Scheme 14

The synthesis of thiosugar-fused bicyclic pyrimidines 57 and 58 with high cis diastereoselectivity at

the ring junction has been developed by Yadav et al. using unprotected aldoses 55, 2-methyl-2-phenyl-1,3-

oxathiolan-5-one 56, and guanidine 46 by a nanoclay catalyst under solvent-free MW irradiation conditions

(Scheme 15).38

H2N NH2

NH+

S

OO

Me

Ph

CHO

(CHOH)n

CH2OH

+MW, K-10 clay

80 °C, 7-12 min

S

N NH

OH

OH

H

H

O

NH2

OH

S

N NH

OH

H

H

O

NH2

OH

OHHO

n = 3

n = 4n = 3, D-xylose

n = 4, D-glucose

55 56 46

57

58

93%

89%

Scheme 15

352


Yadav et al. also reported the above 3-component reactions using 2-phenyloxazol-5(4H)-one 59 instead

of 2-methyl-2-phenyl-1,3-oxathiolan-5-one 56 in the same conditions for synthesis of fused pyrimidines 60 and

61 (Scheme 16).39

H2N NH2

NH+

N

OO

Ph

CHO

(CHOH)n

CH2OH

+MW, K-10 clay

80 °C, 10-12 min

N N

O

NH2

N N

O

NH2

n = 3

n = 4n = 3, D-xylose

n = 4, D-glucose

55 46

OH

OHH

H

H

HPhCOHN

PhCOHN

OH

OH

OH

OH

OH

79%

89%

59

60

61

Scheme 16

A facile 1-pot synthesis of pyrazolo[3,4-d ]pyrimidines 64 by 3-component condensation of 5-chloro-

3-methyl-1-phenyl-1H -pyrazole-4-carbaldehyde 62, 3-methyl-1-(4-aryl)-5-pyrazolone 63, and guanidine hy-

drochloride 8 (Scheme 17) and their antibacterial activity against Mycobacterium tuberculosis H37Rv was

reported by Trivedi et al.40

H2N NH2

NH2+ +

Cl

N

N

NH2

EtOH

62

63 8

64

CHO

NN

ClMe

N

N

Me

R

O

NN

ClMe

N

N

Me

R

Reflux, 3h

56-71%

R = Ph, 2-ClPh, 3-ClPh, 4-MePh, 3-SO3HPh,

4-SO3HPh, 2-Cl-5-SO3HPh, 2,5-Cl2-4-SO3HPh

Scheme 17

2.1.3. Synthesis of 5-carbonitrile compounds

A simple and efficient method for the 1-pot 3-component reaction of aromatic aldehydes 4, methyl cyanoacetate

28, and guanidinium carbonate 6 in the synthesis of 2-amino-4-aryl-1,6-dihydro-6-oxopyrimidine-5-carbonitriles

65 was reported by Bararjanian et al. (Scheme 18). They also attempted a 1-pot, 4-component condensation

reaction of aromatic aldehydes 4, methyl cyanoacetate 28, guanidinium chloride 8, and piperidine 66, in

353


which piperidine acts both as a base and reagent (Scheme 19). The 1H NMR data indicated the formation of

zwitterionic product structures 67.41

NH

NCO32-

Reflux, 3 h

MeOH

4 26 6

65

NC

H2N NH2

NH2

CO2Me

CN

2 NH2

H

O

R O

R

R = H, 4-Br, 4-Cl, 4-NC, 4-

Me, 3-OH, 4-OH, 3-NO2, 4-

NO2, 2,3-Cl2

+ +

36-62%

Scheme 18

N

N

Cl

Reflux

MeOH

4 28 8

67

H2N NH2

NH2

CO2Me

CNO

H

O

RN

R

R = H, 4-Br, 4-Cl, 4-Me, 4-F3C

+ +

43-62%

+NH

NC

H

H

N

N

O

N

RCN

H

H

H

H

NH

66

Scheme 19

Rong et al. also reported an efficient and facile synthesis of 2-amino-4-aryl-1,6-dihydro-6-oxopyrimidine-

5-carbonitriles 65 by the reaction of aromatic aldehydes 4, ethyl cyanoacetate 68, and guanidinium carbonate

6 in the presence of sodium hydroxide and potassium carbonate as catalyst under solvent-free conditions at 70◦C (Scheme 20).42

NH

NCO32-

70 °C, 20-30 min

NaOH/K2CO3

4 68 6

65

NC

H2N NH2

NH2

CO2Et

CN

2 NH2

H

O

R O

R

R= H, 4-Me, 3,4-(Me)2, 4-MeO, 3,4-(MeO)2,

4-F, 3-Cl, 4-Cl, 2,4-Cl2, 3,4-Cl2, 4-Br

+ +

86-93%

Scheme 20

Bhatewara et al. reported a simple and efficient method for synthesis of 2-amino-6-oxo-4-aryl-1,4,5,6-

tetrahydropyrimidine-5-carbonitriles 70 via 3-component condensation of aldehydes 4, ethyl cyanoacetate 68,

354


and guanidinium nitrate 69 using piperidine as a catalyst (Scheme 21).43 They also reported a simple protocol

for preparation of 2-amino-6-aryl-4-oxo-1,4,5,6-tetrahydropyrimidine-5-carbonitriles 71 using the same reactants

and catalyst in solvent-free conditions under microwave irradiation (Scheme 22).44

NH

N

Ar

NO3-

H2O, 60-70 °C

4 68 69 70

NC

H2N NH2

NH2

CO2Et

CN

NH2H

O

O

Ar = Ph, 4-MeOPh, 3,4-(MeO)2Ph, 4-NO2Ph, 2-pyrrolyl,

2-furyl, 3-indolyl, N-methyl-2-pyrrolyl

+ +

83-95%

NH

Ar

Scheme 21

N

NH

Ar

NO3-

MW, 600 WSolvent free

4 68 69 71

NC

H2N NH2

NH2

CO2Et

CN

NH2H

O

O

Ar = Ph, 4-MeOPh, 3,4-(MeO)2Ph, 4-NO2Ph, 2-pyrrolyl,

2-furyl, 3-indolyl, N-methyl-2-pyrrolyl

+ +

79-93%

NH

Ar

Scheme 22

Anbhule and co-workers have developed a simple and efficient approach toward 1-step synthesis of 2-

amino-5-cyano-6-hydroxy-4-aryl pyrimidines 72 using condensation of aromatic aldehydes 4, ethyl cyanoacetate

68, and guanidinium chloride 8 in alkaline ethanol (Scheme 23). The antibacterial study of synthesized

compounds showed good to excellent activity against tested gram-positive and gram-negative bacteria.45

N

N

Ar

Reflux, 1-3 h

NaOH/EtOH

4 68

NC

H2N NH2

NH2

CO2Et

CN

NH2Ar H

O

HO

Ar = Ph, PhCH=CH, 3-NO2Ph, 3,4-(MeO)2Ph, 4-(Me)2NPh, 4-MeOPh,

4-OHPh, 3-ClPh, 2-NO2Ph, 3,4,5-(MeO)3Ph, 2-ClPh, 2-thionyl

Cl+ +

8 72

79-95%

Scheme 23

Val et al. reported a convergent and robust approach for synthesis of 2-aminopyrimidine-5-carbonitriles

76 from 3-component condensation of N -substituted guanidines 75, α -cyanoketones 74, and the corresponding

355


aldehydes 4 (or dimethyl acetals 73) in the presence of DMF at 120 ◦C under microwave irradiation (Scheme

24).46

N

N

R1 (or R2)

Na2CO3, DMF

4

74

NC

H2N N

NH

N

R1 H

O

R1 = Ph, 4-MePh, 3-FPh, 4-FPh, 3-OHPh, 4-OHPh, 2-MeOPh,

4-MeOPh, 3-thionyl, 3-pyridyl, 3-ClPh, 3,5-Cl2Ph, cyclohexyl

+ +

75 7634-86%

or

R2 OMe

OMe

R2 = Me, Et

73

R3

R4

O

NC

X

X = H, 3-Cl, 4-OMeR3 = H, Me, Et, Ph R4 = H, Me

MW, 120 °C45-60 min

X

R3

R4

Scheme 24

The synthesis of 2,6-bis(2-amino-5-cyano-6-phenylpyrimidin-4-yl)pyridine 78 was developed by the re-

action of 2-benzylidene-3-oxopropanenitrile 77 and 2 guanidine 46 molecules in the presence of anhydrous

potassium carbonate (Scheme 25).47

N

OO

CN

Ph

CN

PhK2CO3, EtOH

Reflux, 10 hH2N

NH

NH2+ 2

N

NN

CN

Ph

CN

Ph

N

NH2

N

NH2

72%

77

46

78

Scheme 25

2.1.3.1. Synthesis of 6-amino compounds

Rong and co-workers presented an environmentally friendly and mild method for synthesis of 2,6-diamino-

4-arylpyrimidine-5-carbonitrile derivatives 79 via 1-pot cyclocondensation reaction of aromatic aldehydes 4,

malononitrile 27, and guanidinium carbonate 6 using sodium hydroxide as catalyst at 70 ◦C in solvent-free

conditions (Scheme 26).48

N

NCO3

2-

70 °C

NaOH

4 27 679

NC

H2N NH2

NH2

CN

CN

2 NH2

H

O

RH2N

R

R = H, 4-Me, 4-F, 4-Cl, 3-Cl, 4-Br, 3,4-Cl2, 4-MeO, 3,4-(Me)2

+ +

80-92%

Scheme 26

356


Hekmatshoar et al. also reported an efficient and facile synthesis of 2-amino-4-aryl-1,6-dihydro-6-

oxopyrimidine-5-carbonitriles 79 by the reaction of aromatic aldehydes 4, malonitrile 27, and guanidinium car-

bonate 6 in the presence of ZnO nanoparticles in water.49 A method using granulated copper oxide nanocatalyst

as a mild and efficient reusable catalyst for the 1-pot synthesis of 2-amino-4-aryl-1,6-dihydro-6-oxopyrimidine-

5-carbonitriles 79 under aqueous conditions was also reported by Ahmadi and coworkers by the reaction of

aromatic aldehydes 4, malonitrile 27, and guanidinium carbonate 6.50

Furthermore, another 1-pot synthesis of 2,4-diamino-6-arylpyrimidine-5-carbonitriles 79 was reported by

Deshmukh et al. via condensation of aromatic aldehydes 4, malononitrile 27, and guanidinium chloride 8 in

aqueous medium using tetrabutyl ammonium bromide (TBAB) and potassium carbonate (Scheme 27).51

N

N

Ar

Reflux, 3-4 h

4 27 8 79

NC

H2N NH2

NH2

CN

CN

NH2

Ar H

O

H2N

+ +

63-75%

Cl

TBABK2CO3/H2O

Ar = Ph, PhCH=CH, 3,4-(MeO)2Ph, 4-(Me)2NPh,

4-MeOPh, 4-OHPh, 2-OHPh, 3-ClPh

Scheme 27

2,6-Diamino-4-arylpyrimidine-5-carbonitriles 79 were also synthesized by 3-component reaction of mal-

ononitrile 27, aldehydes 4, and guanidinium chloride 8 in water at reflux or under microwave heating, in the

presence of sodium acetate.52 Sheibani and co-workers reported another method for synthesis of this class of

compounds using high-surface-area MgO as a highly effective heterogeneous base catalyst.53 Moreover, an ef-

ficient 1-pot synthesis of 2,6-diamino-4-arylpyrimidine-5-carbonitriles 79 has been achieved in excellent yields

by the condensation of malononitrile 27, aldehydes 4, and guanidinium chloride 8 using ionic liquid under

controlled microwave irradiation (100 W) at 60 ◦C.54

One-pot synthesis of 6-alkylamino-2,4-diaminopyrimidines 82 using ketene dithioacetals 80,55−56 alkyl

amines 81, and excess guanidinium carbonate 6 was developed under reflux conditions in pyridine (Scheme

28).35

CO32-

H2N NH2

NH2

2N

N

NH2

6

X

CNMeS

MeS

HNR1R2

Y

X

R2N

X = CN, Y = NH2X = SO2Ph, Y = NH2X = CO2Me, Y = OH

HNR1R2 = HNCH2Ph, HNCH(Me)Ph,

OHN HN,

Pyridine

Reflux

81 8280

+ +

70-94%

Scheme 28

357


The reaction of aniline derivatives 42 with ketene dithioacetal 80 gave intermediates 83, which were

reacted with guanidinium carbonate 6 to provide 6-arylamino-2,4-diaminopyrimidines 84 (Scheme 29).35

N

N

NH2CN

CNMeS

MeS

NH2NC

NH

Pyridine, Reflux

CO32-

H2N NH2

NH2

2

CN

CNMeS

NHR

NH2R

R

R = H, 2-MeO, 3-MeO, 4-MeO, 4-Cl

80

42

83 84

6

63-90%

Scheme 29

2.1.3.2. Synthesis of spiro compounds

Ramezanpour et al. developed an efficient protocol for the synthesis of various spiro-2-amino pyrimidinones 86

via a 3-component reaction of N-substituted piperidinones 85, guanidinium carbonate 6, and alkyl cyanoacetates

28 and 68 via domino Knoevenagel-cyclocondensation reaction (Scheme 30). This method has advantages such

as high yields, neutral conditions, and short reaction times. This basic medium was suitable for deprotonation

of alkyl cyanoacetates, which produced the desired alkene intermediate through Knoevenagel condensation on

the reaction with carbonyl compound 85. Michael addition of free guanidine into alkene and then cyclization

led to the synthesis of spiro-2-amino pyrimidinones 86 in good yields.57

N NH

N

O

R = Bn, CH2CH2Ph, PhCHMe

CO32-

NReflux, 20-90 min

MeOH

85 28, X = CO2Me

68, X = CO2Et

6 86

NC

H2N NH2

NH2

X

CN

O

R2

R

NH2

++

70-96%

Scheme 30

An efficient synthesis of spirocyclic 2-aminopyrimidinones 88 was achieved via a domino Michael addition–

cyclocondensation reaction of a cyclic ketone 87, ethyl cyanoacetate 68, and guanidinium carbonate 6 in

methanol (Scheme 31).58

NH

N

O

Reflux, 1-3 h

MeOH

87 68 6 88

NC

CO2Et

CNO

NH2XX

CO32-

H2N NH2

NH2

2

X = CH2, (CH2)2, (CH2)3, MeN, S

+ +

75-85%

Scheme 31

358


2.1.4. Synthesis of 5-alkyl compounds

Maddila et al. developed a simple and efficient approach for synthesis of 2-amino-6-aryl-5-methylpyrimidin-4-ol

derivatives 90 by 3-component condensation of aldehydes 4, ethyl propionate 89, and guanidine hydrochloride

8 using PEG-400 at 75 ◦C (Scheme 32).59

N

N

R

75 °C, 1.5-2 h

4 89 8 90

Me

H2N NH2

NH2

NH2

R H

O

HO

+ +

85-92%

ClPEG-400

R = Ph, 2-ClPh, 3-ClPh, 3,4-(MeO)2Ph, 3,4,5-(MeO)3Ph,

PhCH=CH, 2-NO2Ph, 3-NO2Ph, 4-MePh, 4-OHPh, Et, n-Pr

CO2Et

Me

Scheme 32

2.1.5. Synthesis of dihydropyrimidinone compounds

Gorobets et al. developed 2 different protocols (conventional and microwave conditions) in the synthesis of 2-

amino-5,6-dihydropyrimidin-4(3H)-ones 92. A multicomponent reaction between Meldrum’s acid 91, aliphatic

or aromatic aldehydes 4, and guanidinium carbonate 6 provided easy access to dihydropyrimidinones (Scheme

33). In comparison to the conventional heating method, microwave heating affords more advantages such as

reduced reaction time, low cost, and simplicity in reaction progress, reduced pollution, and higher product

purity.60

CO32-

6

H2N NH2

NH2

2

4 91

R = CHMe2, CH2Ph, Ph, 4-MeOPh, 2-MeOPh, 2,5-(MeO)2Ph,

3-MeO-4-CHF2OPh, 2-ClPh, 4-BrPh, 4-Me2NPh

O O

OO DMF

R

O

H NH

N

NH2

92

O

R

120-130 °C or MW+ +

21-55%

Scheme 33

There are 2 more methods for synthesis of the above 2-amino-5,6-dihydropyrimidin-4(3H)-ones 61.

Mohammadnejad and co-workers reported a 3-component reaction of Meldrum’s acid 91, aromatic aldehyde

4, and guanidinium carbonate 6 in reflux of ethanol that leads to formation of 2-amino-5,6-dihydropyrimidin-

4(3H)-ones 92.61 Mirza-Aghayan and co-workers also developed another method for the synthesis of these

compounds from the 1-pot cyclocondensation of Meldrum’s acid 91, aldehydes 4, and guanidinium carbonate

6 using MCM-41 catalyst functionalized with 3-aminopropyltriethoxysilane (MCM-41-NH2) as an efficient

nanocatalyst in DMF.62

359


2.2. Synthesis of 2-iminopyrimidine compounds

2-Iminopyrimidines 94 were synthesized by Akbas et al. using 3-component cyclocondensation of arylaldehydes

4, dibenzoylmethane 93, and guanidine 46 (Scheme 34). The electrochemical properties of the novel systems

were investigated by cyclic voltammetry (CV) and differential pulse voltammetry (DPV).63

H2N NH2

NH

Ph

O

++Ph

O

R = H, 4-Cl, 3-NO2, 4-CN

NaHCO3/DMF

70 °C, 5 h

H

O

NH

NH

NHPh

Ph

OH

R

R

4 93 4694

Scheme 34

Multicomponent Biginelli reaction of 3-(aryl)-1-phenyl-1H -pyrazole-4-carbaldehydes 95,64 ethyl acetoac-

etate 96, and guanidinium chloride 8 was reported by Shah et al. (Scheme 35). All synthesized dihydropyrim-

idines 97 were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv.65

H2N NH2

NH2

EtO

O

+ +Me

O

N N

CHOR

N N

R

NH

NH

NHMe

EtO

O

R = F, Cl, Br, NO2, CH3

ClEtOH

Reflux, 9 h

95

96 8

97

Scheme 35

4,5,6-Triphenyl-1,2,3,4-tetrahydropyrimidine derivatives 99 were synthesized by 1-pot reaction of 1-(4-

(methylthio)phenyl)-2-phenylethanone 98, aromatic aldehydes 4, and guanidinium chloride 8 in the presence

of potassium carbonate in ethanol (Scheme 36). In this reaction, at first chlorination of phenyl acetic acid by

thionyl chloride yielded phenylacetyl chloride, which reacted with thioanisole in dichloromethane in the presence

of AlCl3 to give 1-(4-(methylthio)phenyl)-2-phenylethanone 98. All the synthesized compounds were tested for

their ability to inhibit cyclooxygenase-2 (COX-2).66

360


O

SMe

H

O

RH2N NH2

NH2

++

R

K2CO3

EtOH

Cl

NH

NH

SMe

NH

4 9899

8

R = H, 4-Me, 4-OH, 4-Cl, 2-NO2, 3-NO2,

4-MeO, 3,4-(MeO)2, 2,5-(MeO)2

Scheme 36

A facile synthesis of novel trifluoromethyl derivatives of 4,4’-(1,4-phenylene)-bis(tetrahydro-pyrimidin-

2(1H)-imine) 102 was reported by Azizian et al. via 1-pot 3-component condensation of terephthalaldehyde

100 with guanidine 46 and fluorinated 1,3-dicarbonyl derivatives 101 using chlorotrimethylsilane (TMSCl) as

catalyst (Scheme 37).67

H2N NH2

NH+ +

OHC

CHOF3C

O O

R

TMSCl/MeCN

r.t., 60 min

HN NH

NHHN

HOH

F3C

CF3

HOHOR

NH

O R

NHR = Me, 2-thienyl

100 101 46

102

80-82%

Scheme 37

Miri et al. reported a Biginelli condensation reaction of terephthalaldehyde 100, acetylacetone 103, and

guanidine 46 using chlorotrimethylsilane under microwave irradiation for 1-pot synthesis of 4,4’-(1,4-phenylene)-

bis(3,4-dihydropyrimidin-2(1H)-imine) 104 (Scheme 38). The cytotoxicity of this compound was evaluated on

5 different human cancerous cell lines.68

H2N NH2

NH++

OHC

CHO

O O

Me 100 °C, 4 min

HN NH

NHHN

NH

NH

Me

Me

Me O

MeOTMSCl, MW

Me

100 103 46

104

85%

Scheme 38

Pyrimidine derivative 105, produced by condensation of 4-hydroxy benzaldehyde 4 with guanidine 46 and

ethyl acetoacetate 96 (Scheme 39, A), has been condensed with acid chloride of phenyl substituted pyrazolone

361


carboxylic acid 107, which was synthesized by reaction of phenyl hydrazine 106 with ethyl acetoacetate 96 and

then alkaline oxidation with KMnO4 /KOH (Scheme 39, B) to give compound 108 (Scheme 39, A+B).69

O

H

H2N NH2

NH

+

HN

NH

HN Me

HO

Me OEt

O O

OH

O

OEtCondensation

Me

EtO

O

O

Condensation

HNNH2

+N

HNO

Me

KMnO4/KOHN

HNO

O

OH

NHN

O

O

Cl

SO2Cl

CondensationN

NHN Me

OH

O

OEt

O

O

N NH

O

HN N

O

446

96

105

106 96107

108

HN

NH

HN Me

OH

O

OEt

105

NHN

O

O

Cl

+

107

A

B

A + B

Scheme 39

2.3. Synthesis of triazine compounds

2,6-Diamino-3,6-dihydro-6-aryl-1,3,5-triazine 109 was synthesized by reaction of aromatic aldehydes 4 with 2 or

more equivalents of guanidinium chloride 8 in the presence of sodium methoxide in methanol by Ujjinamatada

et al. (Scheme 40). By this reaction, they have discovered a novel functional group transformation involving

selective conversion of an ester group of imidazole ring 110 into the corresponding amide 111, while simul-

taneously protecting the aldehyde group as dihydrotriazine (Scheme 41). In this transformation, alternative

dihydrodiazepines 112 were not synthesized.70

362


H

O

R

+

H2N NH2

NH2 NaOMe/MeOH

Reflux, 12 h

R

N

NHN

NH2

NH2

R = H, 2,4-(MeO)2

61-67%

4 8 109

2Cl

Scheme 40

H

O

+

H2N NH2

NH anhydrous EtOH

Reflux, 15 h

R = Ph, OCH2Ph

61-66%

O

OEt

N

N

O

NH2

N

N

N

NHN

NH2

NH2

R

R

N

N

R

NH

N

O

NH2

HN

NH

NH2

111

112

110 46

2

Scheme 41

The respective compounds 111 and 112 have the same molecular formula, the same methine signal

of either the dihydrotriazine or the dihydrodiazepine ring, and with tautomerization the same number of

amino/imino groups exchangeable with D2O. In order to resolve this structural ambiguity, an unambiguous

synthesis was performed of 1 of the 2 amide–triazines 111 by the reaction of amide–aldehyde 113 with excess

guanidine 46 in methanol at reflux (Scheme 42).70

H2N NH2

NH

Reflux, 15 h

O

NH2

N

N

N

NHN

NH2

NH2

111

46

MeOH

O

NH2

N

N

H

OOPh O

Ph

113

+ 2

Scheme 42

363


Gund et al. reported the isolation of a fully aromatic product s-triazine 114 in low yield from a complex

mixture of products by the reaction of excess benzaldehyde 4 (used as a solvent) with guanidinium carbonate

6 (Scheme 43).71

O

HCO3

2-

H2N NH2

NH2

2

+

64

Benzaldehyde

Reflux N

N

N

NH2

NH2114

30%

2

Scheme 43

2.4. Synthesis of miscellaneous compounds

Zomordbakhsh et al. synthesized 2,4,6-triarylpyridine derivatives 116 by the reaction of chalcone derivatives

115 with guanidine 46 and acetophenones 5 in solvent-free conditions (Scheme 44).72

O

Me

H2N NH2

NH

+

R1 R3

O

R2

+Solvent-free

MW, 600 W, 4 min N

R3

R1 R2

R1 = Ph, 4-Me, 4-Cl, 4-MeO

R3 = Ph, 2-Me, 4-Me, 4-Cl, 4-MeO, 4-N(Me)2, 4-NO2

R2= Ph, 4-Me, 4-Cl, 4-MeO

5 11546

116

Scheme 44

Jalani et al. developed an efficient 1-pot domino method for the synthesis of 2-aminothiazoles 120 using

isothiocyanates 117, tetramethylguanidine 118, and halomethylenes 119 in DMF (Scheme 45).73

N(Me)2

N(Me)2

HN+R1 N C S N(Me)2

N(Me)2

N

SNH

R1

N

S

N(Me)2

NH

R1

R2DMF

65-76%

DMF

2-3 h8-24 h

R1 = Ph, Bn, CO2EtNO

O

OO

Br

Br R2

Br R2 = or

O

Br

117 118

119

120

Scheme 45

Jalani et al. also reported another 1-pot domino method for synthesis of 1,2,4-oxadiazol-3-amines 122

using isothiocyanates 117, tetramethylguanidine 118, and hydroxylamine 121 in DMF (Scheme 46).74

364


N(Me)2

N(Me)2

HN+R N C S N(Me)2

N(Me)2

N

SNH

R

N

NO

N(Me)2

NH

R

67-86%

DMF

20-25 °C,1 h

R = Ph, 4-ClPh, 4-MePh

NH2OH.HCl

Et3N, AgNO3r.t. 3-4 h117

118122

121

Scheme 46

The reaction of 4-chlorobenzaldehyde 4 and guanidinium carbonate 6 in the presence of sodium methoxide

in ethanol after acidification with concentrated HCl gave noncyclic l-(p -chlorobenzoyl)-3-(p-chlorobenzyl)guanidine

HCl 123 (Scheme 47).71

2) HCl

1) NaOMe/EtOHO

H

Cl

CO32-

H2N NH2

NH2

2

2 +

O

NH

Cl

NH

NH

Cl

HCl

64 12342%

r.t., 4 h

Scheme 47

Yavari et al. synthesized stable charge-separated tetramethylguanidinium-barbituric acid zwitterionic

salts 125 through a 1-pot 3-component reaction of aromatic aldehydes 4, N,N’-dimethylbarbituric acid 124,

and N,N,N’,N’-tetramethylguanidine 118. They also studied dynamic NMR of zwitterionic salts as a result of

restricted rotation around the Me2N–C bonds of the guanidine functional group (Scheme 48).75

118

(Me)2N N(Me)2

NH

r.t., 81-93%Ar

O

H

4 124

Ar = Ph, 4-MePh, 2-MePh, 4-ClPh, 2-ClPh,

4-FPh, 2-FPh, 2-NO2Ph, 2-OHPh, 4-MeOPh

+ +CH2Cl2N N

O O

O

MeMe

N N

O O

O

MeMe

Ar NH

(Me)2N NH(Me)2

125

Scheme 48

Kolos et al. reported a thermally activated or microwave-induced 1-pot 3-component condensation of

arylglyoxal hydrates 126, 1,3-dimethylbarbituric acid 124, and guanidine salts 6 and 8 for synthesis of 5-(2-

amino-5-aryl-1H -imidazol-4-yl)-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H ,3H)-dione 127. Formation of the

imidazole ring involved intermediates 128 that after heating in 2-propanol gave the desired imidazole 127. The

acetylation of pyrimidinediones 127 in acetic anhydride gave acetyl derivatives 129 (Scheme 49).76

365


H2N NH2

NH2

+

Cl-

N

NO

O

Me

Me

O OHO

OH

, 2-PrOH, ∆, 1 hr.t., 24 h, 55-70%

or

H2N NH2

NH2, EtOH, AcOH, MW

2

CO32-

N

NO

O

Me

Me

OH

N

NH

NH2

Ac2O

∆, 30 min

N

NO

O

Me

Me

OH

N

NH

NH

Me

O

2-PrOH, AcOH, 50 °C

N

NO

O

Me

Me

O

N

O

NH2

NH2 2-PrOH,∆ ,1h

R

R = H, 4-MeO, 4-Cl, 4-Br, 4-NO2

R

R

H2N NH2

NH2

2

CO32-

150 °C, 10 min, 65-72%

R

124 126

6

8

127

128

129

Scheme 49

The multicomponent condensation of guanidinium sulfate 130 with CH2O 131 and H2S 132 in more than

70 ◦C and in the concentration of the thiomethylating mixture (130:131:132 = 1:10:9) led to the formation of

target macroheterocycle 133 in 10% yield along with 1,3,5,7-oxatrithiocane 134 (Scheme 50). In the temperature

range from 20 to 60 ◦C the guanidinium sulfate salt 130 is not involved in the reaction with CH2O and H2S.77

SO42-

H2N NH2

NH2

2

130

+ CH2O H2S+70 °C

S

O

S

O

NH

S

NH

S

S

NH

S

HN

SHN

S

S

NH

S

+

131 132

133 (10 %)

134 (56 %)

Scheme 50

Synthesis of aza crown 137 was carried out by 3-component condensation of 1,5-bis(2-formylphenoxy)-

3-oxapentane 135, ammonium acetate 136, and guanidine 46 in ethanol and acetic acid (Scheme 51).78

366


H2N NH2

NH

r.t., 13 h

46

EtOH, AcOH

135

+

O

CHO

O

O

OHCNH

HN NH

NH

O O

O

+NH4OAc

136

137

28%

Scheme 51

3. Guanidine as a catalyst

Guanidinium chloride 8 has been found to be a highly efficient catalyst for 1-pot 3-component Strecker reaction

between various aldehydes 4, amines 81, and trimethylsilyl cyanide 137 for synthesis of α -aminonitriles 138

(Scheme 52).13

H2N NH2

NH2 Cl

R1 H

O

R2NR3

H

Me3SiCN

NR3R2

CNR1MeOH, 40 °C, 1h

R1 = t-Bu, Bn, n-pentyl, Ph, 4-ClPh, 2-furyl,

4-pyridyl, cinnamyl, i-propyl, 4-MeOPh

R2= H, Et, Bn R3 = Ph, Et, Bn

++

4 81 137

8

82-98% 138

Scheme 52

Guanidinium chloride 8 is also an active and simple catalyst for Mannich-type reaction between various

aldehydes 4, acetophenone 5, and aniline 42 for synthesis of β -carbonyl compounds 139 (Scheme 53).12

H2N NH2

NH2

O

H

R

O

Me

4 5

R = H, 4-Me, 4-F, 4-Cl, 4-NO2, 4-MeO

ClNH2

O HN

R

r.t., 3-4 h

42

8

80-90%

139

Scheme 53

Baghbanian et al. have described an efficient methodology for synthesis of Hantzsch dihydropyridines

141 by 3-component condensation of aldehydes 4, methyl acetoacetate 140 (or ethyl acetoacetate 96), and

ammonium acetate 136 by guanidinium chloride 8 as catalyst (Scheme 54). They also used guanidinium

chloride 8 as catalyst for synthesis of octahydroquinoline derivatives 143 through Hantzsch reaction of aldehydes

367


4, methyl acetoacetate 140 (or ethyl acetoacetate 96), dimedone 142, and ammonium acetate 136 (Scheme

55).79

H2N NH2

NH2

R1

O

H

4

R1 = Ph, 4-ClPh, PhCH=CH, cyclohexyl, 2-Furyl,

4-MePh, 4-BrPh, 4-OHPh, 4-NO2Ph, n-pentyl

Cl

EtOH, r.t., 3 h

8

95-98%

Me

O O

OR2NH4OAc

NH

O

R2O

O

OR2

R1

2

136140, R2 = Me

96, R2 = Et 141

Scheme 54

H2N NH2

NH2

R1

O

H

4

R1 = Ph, 4-ClPh, PhCH=CH, 2-Furyl, 4-MePh, 4-MeOPh,

4-OHPh, 4-NO2Ph, 3-pyridyl, 4-BrPh, n-Pr

Cl

EtOH, r.t., 3 h

15

75-95%

Me

O O

OR2NH4OAc

NH

O

R2O

O

R1

O

O

140, R2 = Me

96, R2 = Et142

143

136

Scheme 55

4. Guanidine as a solvent

1,1,3,3-Tetramethylguanidine acetate [TMG][Ac] ionic liquid 147 was used as solvent for the 3-component

reaction between ninhydrin 144, sarcosine 145, and 1-benzyl/methyl-3,5-bis[(E)-arylidene]-piperidin-4-ones

146 for synthesis of dispiro heterocycles 148 (Scheme 56). The TMG-based ionic liquid is a reusable and

environmentally benign solvent for synthesis of dispiropyrrolidines in high yields.80

(Me)2N N(Me)2

NH2

O

O

OH

OH H3C

HN COOH

NR

ArH

ArH

OO

O

NCH3

ArH

NR

O

Ar

+ +

OAc

R = Me, CH2Ph Ar = Ph, 4-MePh, 4-MeOPh, 4-ClPh,

4-BrPh, 4-FPh, 3,4-(MeO)2Ph

80 °C, 3-6 h

88-92%

144

145

146

147

148

Scheme 56

368


5. Conclusion

In this review, applications of guanidine and its salts in multicomponent reaction have been studied. Guanidine

can be used as catalyst and also as a reactant in the synthesis of heterocycles in conventional, microwave, or

solvent-free conditions. In most cases, using a base with guanidine salts is necessary for synthesis of heterocyclic

compounds. Because of the ionic structure of guanidine salts, using microwave irradiation will be suitable for

synthesis of heterocylic compounds.

Acknowledgment

We are grateful for financial support from the Research Council of Alzahra University.

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IntroductionGuanidine as a reagentSynthesis of 2-aminopyrimidine compoundsSynthesis of 4,6-diaryl compoundsSynthesis of pyrimidine-fused ring systemsSynthesis of 5-carbonitrile compoundsSynthesis of 5-alkyl compounds Synthesis of dihydropyrimidinone compounds

Synthesis of 2-iminopyrimidine compoundsSynthesis of triazine compoundsSynthesis of miscellaneous compounds

Guanidine as a catalystGuanidine as a solventConclusion

application of guanidine and its salts in multicomponent reactions · guanidine, also called...

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