application of guanidine and its salts in multicomponent...
TRANSCRIPT
Turk J Chem
(2014) 38: 345 – 371
c⃝ TUBITAK
doi: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]
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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
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RAHIMIFARD et al./Turk J Chem
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
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RAHIMIFARD et al./Turk J Chem
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-
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RAHIMIFARD et al./Turk J Chem
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
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RAHIMIFARD et al./Turk J Chem
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
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RAHIMIFARD et al./Turk J Chem
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
RAHIMIFARD et al./Turk J Chem
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
RAHIMIFARD et al./Turk J Chem
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
RAHIMIFARD et al./Turk J Chem
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
RAHIMIFARD et al./Turk J Chem
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
RAHIMIFARD et al./Turk J Chem
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
RAHIMIFARD et al./Turk J Chem
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
RAHIMIFARD et al./Turk J Chem
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
RAHIMIFARD et al./Turk J Chem
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
RAHIMIFARD et al./Turk J Chem
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
RAHIMIFARD et al./Turk J Chem
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
RAHIMIFARD et al./Turk J Chem
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
RAHIMIFARD et al./Turk J Chem
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
RAHIMIFARD et al./Turk J Chem
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
5 115 46
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
RAHIMIFARD et al./Turk J Chem
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
RAHIMIFARD et al./Turk J Chem
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
RAHIMIFARD et al./Turk J Chem
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
RAHIMIFARD et al./Turk J Chem
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
RAHIMIFARD et al./Turk J Chem
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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