Application of guanidine and its salts in multicomponent reactions

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.

Turk J Chem (2014) 38: 345 371 ă ITAK ˙ c TUB ⃝ Turkish Journal of Chemistry http://journals.tubitak.gov.tr/chem/ doi:10.3906/kim-1307-38 Research Article Application of guanidine and its salts in multicomponent reactions Mahshid RAHIMIFARD, Ghodsi MOHAMMADI ZIARANI∗, Boshra MALEKZADEH LASHKARIANI Department 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 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 Trimethoprim 1, sulfadiazine 2, and Gleevec (imatinib mesilate) 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 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 Me N NH2 MeO H2N N MeO N N H N NH2 S O O N N N N N HN H N OMe O Me 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: gmziarani@hotmail.com 345 RAHIMIFARD et al./Turk J Chem Using guanidine and its salt as reagent in multicomponent reactions usually leads to the formation of guanidinecontaining 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 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 by multicomponent reaction of aromatic aldehydes 4, acetophenones 5, and guanidinium carbonate in the presence of sodium hydroxide under solvent-free conditions was reported by Zhuang et al (Scheme 1) 14 R2 O O H Me + NH2 + NH2 H2N R1 R2 CO322 NaOH 70 ° C, 25 88-96% N R1 R1 = H, 4-Me, 4-F, 4-Cl, 4-Br, 2-Cl, 2,4-Cl2, 4-MeO N NH2 R2 = H, 4-Cl, 4-MeO Scheme 4,6-Diaryl amino pyrimidines were also synthesized by 3-component condensation of aromatic aldehydes 4, acetophenones 5, and guanidinium chloride 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 2,4thiazolidinedione acetic acid with diaryl amino pyrimidines in DMF using N,N-dicyclohexylcarbodimide (DCC) at room temperature (Scheme 2) 15 Pyridylpyrimidine is a N,N’-chelating ligand that has 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 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 (or 1-naphthaldehyde 15), 2-acetylnaphthalene 13 (or acetophenones 5) with guanidinium carbonate in the presence of sodium hydroxide under solvent-free conditions (Schemes and 5) 17 346 RAHIMIFARD et al./Turk J Chem R2 O O H Me + R1 + H2N NH2 Aq PEG-400, KOH Cl R2 N r.t., 10 h 82-89% NH2 R1 R1 = 4-Me, 4-MeO, 4-F, 2-Cl, 4-Cl, 4-Br NH2 N R2 = H, 4-OH, 4-MeO O O H N O DCC, DMF r.t h 71-78% S HO R2 N NH N R1 O NH S O O 10 Scheme R O O H + Me N NH2 + NH2 H2N R CO322 11 NaOH N 70 ° C, 45 89-96% N N NH2 12 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 Scheme 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 This amino-dihydropyrimidines can readily react under microwave irradiation and solvent-free conditions, with 3formylchromone 19 or diethyl(ethoxymethylene)malonate 20 to yield novel pyrimido[1,2-a]pyrimidines 21 or 22, respectively (Scheme 6) 18 347 RAHIMIFARD et al./Turk J Chem R O O H Me + NH2 + NH2 H2N R CO322 13 NaOH 70 ° C, 30 81-91% N NH2 N 14 R = 4-Me, 4-MeO, 3,4-(MeO)2, 4-F, 4-Br, 4-Cl, 2,4-Cl2, 3,4-Cl2 Scheme O H O Me + NH2 + NH2 H2N R NaOH CO322 15 N 70 ° C, 30 81-91% N NH2 16 R R = H, 4-Me, 4-MeO, 2,4-Me2, 3-Cl, 2,4-Cl2 Scheme O O O O CO2Et O + H Ar Ar + NH2 H2N 17 70 ° C, h 75-85% Ph N N O N 21 N Ph EtO2C H Cl EtO2C NH2 NaHCO3/DMF OH Ar H H 19 N H NH2 Ar H EtO2C 18 Ar = Ph, 4-MePh, 4-MeOPh, 4-ClPh, 2-thienyl CO2Et Ph EtO2C O CO2Et N N 22 N H H H EtO 20 Scheme 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[1,2a]pyrimidine that developed numerous biologically active compounds Reaction of β -keto-ester 23, thiophene348 RAHIMIFARD et al./Turk J Chem 2-carboxaldehyde 24, and guanidinium carbonate followed by reaction with 3-formylchromone 19 led to the formation of pyrimido[1,2-a]pyrimidine 25 (Scheme 7) 19 O O O C6F13 O Ph H CHO O + NH2 S + NH2 H2N O CO32- OH O N O Ph N N 25 24 O 43% 23 S C6F13 19 Scheme The heterocyclic pyrido[2,3-d ]pyrimidines ring system represents several biological activities Some analogues 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 multifunctionalized 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 was reported by Borrell et al (Scheme 8) 24,25 CO2Me + R1 R2 CN + X R2 NH2 NH2 H2N CO32- NaOMe/MeOH MW, 140 ° C, 10 26 27, X = CN 28, X = CO2Me Y R1 O N N H N NH2 29 R1 = H, Me R2 = H, Me, Ph X = CN, Y = NH2 X = CO2Me, Y = OH Scheme Use of guanidinium carbonate in the synthesis of pyrido[2,3-d]pyrimidines was previously described by Borrell et al in 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-5,6dihydropyrido[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 RAHIMIFARD et al./Turk J Chem NH R2 NaOMe/MeOH R1 CN R1 CO2Me 31 CN OMe N H O CN 27 NHR3 H2N 30 R2 NH R1 1,4-dioxane MW, 140 °C 10 N N H O R3 NH2 N 32 NaOMe/MeOH NH R2 26 R2 NHR3 H2N NH2 R1 31 R1 = H, Me, 2,6-Cl2Ph R2 = H, Me R3 = Ph, 4-ClPh N N H O NHR3 N 33 Scheme 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 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 O NH O CO2Me CN NH2 NaOMe/MeOH + + CO32Reflux, 36 h NH2 CO2Me H2N O 55% 34 28 NH N H 35 N O N N NH2 O NH2 OH OH HO 36 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 by Tominaga et al (Scheme 12) 35 350 RAHIMIFARD et al./Turk J Chem O R n = 0,1 37 NaOH, 70 ° C,15 90-97% n N N O NH2 H + NH2 H2N R CO32- NH2 39 O R n = 0,1 38 n R = H, 4-Me, 4-MeO, 3,4-Me2, 3,4(MeO)2, 4-Br, 4-Cl, 3-Cl, 3,4-Cl2, 4-F NaOH, 70 ° C,15 90-98% N N R NH2 40 Scheme 11 NH2 O NH2 MeS + + MeS H2N NH2 CO322 O 41 42 Pyridine Reflux 92% O HN N N NH2 43 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 (Scheme 13) and its antagonist activity of A 2A adenosine receptor were studied by Matasi et al 36 O O N Me 44 H + NH2 Cl + HN N NH2 H2N O NaOH EtOH N NH2 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 O O O HN O O O O N H 49 N H 49 NH NH HN NH2 N HN 53 NH NH O NH 47 O O h, 75% NH HN NH2 H2N HCl/EtOH Reflux 46 NH2 N NH O O HN O O O O h, 82% O O 51 48 O O HCl/EtOH Reflux O O O 50 50 h, 78% h, 84% O O NH NH2 N O 54 NH2 N O 52 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-1,3oxathiolan-5-one 56, and guanidine 46 by a nanoclay catalyst under solvent-free MW irradiation conditions (Scheme 15) 38 OH n=3 O 93% H (CHOH)n + Ph Me CH OH S O + O NH2 H2N NH2 MW, K-10 clay NH 56 57 HO OH OH 46 n=4 n = 3, D-xylose n = 4, D-glucose 89% O H N S H NH NH2 Scheme 15 352 OH 80 ° C, 7-12 55 H NH N CHO OH S OH 58 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 n=3 79% PhCOHN H H OH O OH N N CHO N (CHOH)n + O + O Ph CH2OH NH2 80 °C, 10-12 H2N 59 55 NH2 60 MW, K-10 clay NH OH 46 n=4 n = 3, D-xylose n = 4, D-glucose 89% PhCOHN H H OH OH O N N OH NH2 OH 61 Scheme 16 A facile 1-pot synthesis of pyrazolo[3,4-d]pyrimidines 64 by 3-component condensation of 5-chloro3-methyl-1-phenyl-1H -pyrazole-4-carbaldehyde 62, 3-methyl-1-(4-aryl)-5-pyrazolone 63, and guanidine hydrochloride (Scheme 17) and their antibacterial activity against Mycobacterium tuberculosis H37Rv was reported by Trivedi et al 40 Me N N Me + Cl CHO N NH2 Cl + N R O NH2 H2N 63 N N EtOH Reflux, 3h 56-71% Me Me N N N R 62 Cl N NH2 64 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 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 H NMR data indicated the formation of zwitterionic product structures 67 41 R O H CN NH2 + + R NH2 H2N CO2Me NC Reflux, h 36-62% O 26 MeOH CO32- N NH2 N H 65 R = H, 4-Br, 4-Cl, 4-NC, 4Me, 3-OH, 4-OH, 3-NO2, 4NO2, 2,3-Cl2 Scheme 18 O CN H + R + CO2Me H2N 28 Cl NH2 NH + Reflux 43-62% NH2 MeOH 66 R = H, 4-Br, 4-Cl, 4-Me, 4-F3C R H O H N NC N N H N N N H O H H N H R CN 67 Scheme 19 Rong et al also reported an efficient and facile synthesis of 2-amino-4-aryl-1,6-dihydro-6-oxopyrimidine5-carbonitriles 65 by the reaction of aromatic aldehydes 4, ethyl cyanoacetate 68, and guanidinium carbonate in the presence of sodium hydroxide and potassium carbonate as catalyst under solvent-free conditions at 70 ◦ C (Scheme 20) 42 R O H CN + CO2Et R 68 NH2 + H2N NH2 CO322 NaOH/K2CO3 70 ° C, 20-30 86-93% NC O N N H NH2 65 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 Scheme 20 Bhatewara et al reported a simple and efficient method for synthesis of 2-amino-6-oxo-4-aryl-1,4,5,6tetrahydropyrimidine-5-carbonitriles 70 via 3-component condensation of aldehydes 4, ethyl cyanoacetate 68, 354 RAHIMIFARD et al./Turk J Chem Hekmatshoar et al also reported an efficient and facile synthesis of 2-amino-4-aryl-1,6-dihydro-6oxopyrimidine-5-carbonitriles 79 by the reaction of aromatic aldehydes 4, malonitrile 27, and guanidinium carbonate 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-oxopyrimidine5-carbonitriles 79 under aqueous conditions was also reported by Ahmadi and coworkers by the reaction of aromatic aldehydes 4, malonitrile 27, and guanidinium carbonate 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 in aqueous medium using tetrabutyl ammonium bromide (TBAB) and potassium carbonate (Scheme 27) 51 O Ar CN + H NH2 Cl + NC Reflux, 3-4 h NH2 H2N CN Ar TBAB K2CO3/H2O 63-75% 27 H2N N NH2 N 79 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 malononitrile 27, aldehydes 4, and guanidinium chloride 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 efficient 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 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 was developed under reflux conditions in pyridine (Scheme 28) 35 Y MeS NH2 CN + MeS HNR1R2 + X 80 81 NH2 H2N CO322 HNR1R2 = HNCH2Ph, HNCH(Me)Ph, HN O , HN Pyridine X Reflux 70-94% R2N N N NH2 82 X = CN, Y = NH2 X = SO2Ph, Y = NH2 X = CO2Me, Y = OH 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 to provide 6-arylamino-2,4-diaminopyrimidines 84 (Scheme 29) 35 NH2 NH2 R MeS CN MeS CN H2N MeS 42 NC Pyridine, Reflux R 63-90% CN R 80 NH2 CN NH NH2 CO32N N H NH2 N 84 83 R = H, 2-MeO, 3-MeO, 4-MeO, 4-Cl 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 O O + CO322 Reflux, 20-90 70-96% R N NH2 N H N 28, X = CO2Me 68, X = CO2Et 85 NH2 H2N X N R NC MeOH NH2 CN + 86 R = Bn, CH2CH2Ph, PhCHMe 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 in methanol (Scheme 31) 58 O O CN + X 87 NH2 + CO2Et NH2 H2N 68 CO322 Reflux, 1-3 h 75-85% X N N H 88 X = CH2, (CH2)2, (CH2)3, MeN, S Scheme 31 358 MeOH NC NH2 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 using PEG-400 at 75 ◦ C (Scheme 32) 59 R O R Me + H 75 °C, 1.5-2 h HO NH2 Cl + NH2 H2N CO2Et PEG-400 Me N NH2 N 85-92% 89 90 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 Scheme 32 2.1.5 Synthesis of dihydropyrimidinone compounds Gorobets et al developed different protocols (conventional and microwave conditions) in the synthesis of 2amino-5,6-dihydropyrimidin-4(3H)-ones 92 A multicomponent reaction between Meldrum’s acid 91, aliphatic or aromatic aldehydes 4, and guanidinium carbonate 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 R O O + H R O O O NH2 + H2N NH2 CO322 91 DMF 120-130 °C or MW 21-55% N O N H NH2 92 R = CHMe2, CH2Ph, Ph, 4-MeOPh, 2-MeOPh, 2,5-(MeO)2Ph, 3-MeO-4-CHF2OPh, 2-ClPh, 4-BrPh, 4-Me2NPh Scheme 33 There are 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 in reflux of ethanol that leads to formation of 2-amino-5,6-dihydropyrimidin4(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 using MCM-41 catalyst functionalized with 3-aminopropyltriethoxysilane (MCM-41-NH ) 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 R O O H O O NH + + Ph Ph R NaHCO3/DMF 70 ° C, h NH2 H2N H NH Ph Ph N H 46 93 NH 94 R = H, 4-Cl, 3-NO2, 4-CN Scheme 34 Multicomponent Biginelli reaction of 3-(aryl)-1-phenyl-1H -pyrazole-4-carbaldehydes 95, 64 ethyl acetoacetate 96, and guanidinium chloride was reported by Shah et al (Scheme 35) All synthesized dihydropyrimidines 97 were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv 65 O N N CHO O NH2 + + Me EtO R NH2 H2N 96 Cl N N EtOH O Reflux, h Me 95 R EtO NH N H NH 97 R = F, Cl, Br, NO2, CH3 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 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 AlCl 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 R O O H + + R S Me K2CO3 NH2 EtOH H2N 98 NH2 Cl NH NH N H Me S 99 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-pyrimidin2(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 NH OHC HN F3C TMSCl/MeCN O O NH HO + + R H2N F C NH2 r.t., 60 R CHO 80-82% 46 100 101 NH H O OH CF3 NH HN 102 R = Me, 2-thienyl R O H NH 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 different human cancerous cell lines 68 NH HN O OHC O NH + CHO 100 + Me Me 103 TMSCl, MW NH2 100 °C, 85% H2N NH O Me Me Me Me O HN 46 104 NH NH Scheme 38 Pyrimidine derivative 105, produced by condensation of 4-hydroxy benzaldehyde 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 KMnO /KOH (Scheme 39, B) to give compound 108 (Scheme 39, A+B) 69 OH O O Me NH H A O OEt O 96 + NH2 H2N HO HN Condensation 46 OEt HN Me N H 105 OH Me HN Cl O O NH2 Me O + B HN N Condensation O HN KMnO4/KOH N O HN O N SO2Cl O EtO 106 96 107 OH OH Cl O O A+B + HN HN O Condensation HN N O OEt N H Me O O N N NH HN OEt N Me O O HN N 105 107 108 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 with or more equivalents of guanidinium chloride 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 simultaneously 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 NH2 O H + R NH NH2 N Reflux, 12 h 61-67% NH2 H2N N NaOMe/MeOH NH2 Cl R 109 R = H, 2,4-(MeO)2 Scheme 40 NH2 R NH N 61-66% R N NH2 N NH2 N O N O H OEt N + NH anhydrous EtOH Reflux, 15 h NH2 H2N 111 NH O R 46 110 NH2 HN N N N NH NH2 R = Ph, OCH2Ph O 112 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 D O In order to resolve this structural ambiguity, an unambiguous synthesis was performed of of the amide–triazines 111 by the reaction of amide–aldehyde 113 with excess guanidine 46 in methanol at reflux (Scheme 42) 70 NH2 Ph O O N NH H NH2 N + H2N NH2 MeOH Reflux, 15 h 46 O Ph N O N NH NH2 N NH2 N O 113 111 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 (used as a solvent) with guanidinium carbonate (Scheme 43) 71 O NH2 NH2 H + Benzaldehyde CO32- NH2 H2N N N Reflux 30% N NH2 114 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 in solvent-free conditions (Scheme 44) 72 R3 O O NH Me + + R3 R1 R2 NH2 H2N MW, 600 W, N 46 115 Solvent-free R1 R2 = Ph, 4-Me, 4-Cl, 4-MeO R1 = Ph, 4-Me, 4-Cl, 4-MeO R2 116 R3 = Ph, 2-Me, 4-Me, 4-Cl, 4-MeO, 4-N(Me)2, 4-NO2 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 R1 N C S N(Me)2 + HN 117 Br R2 119 N(Me)2 DMF N N(Me)2 2-3 h R1 118 N H N(Me)2 S DMF 8-24 h R1 N H 65-76% N(Me)2 N R2 S 120 R1 = Ph, Bn, CO2Et Br N O Br R2 = Br O O O or O 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 R N C S + DMF N(Me)2 HN NH2OH.HCl 121 N(Me)2 117 20-25 °C,1 h R 118 N N H N(Me)2 S N(Me)2 N Et3N, AgNO3 R N r.t 3-4 h H 67-86% O N 122 R = Ph, 4-ClPh, 4-MePh Scheme 46 The reaction of 4-chlorobenzaldehyde and guanidinium carbonate 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 O H + Cl NH2 NH2 H2N CO32- 2) HCl 42% NH O 1) NaOMe/EtOH r.t., h HCl N H N H Cl Cl 123 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 Me N–C bonds of the guanidine functional group (Scheme 48) 75 O Me O Me O Ar H + N N O Me + NH (Me)2N N(Me)2 O 124 118 Ar = Ph, 4-MePh, 2-MePh, 4-ClPh, 2-ClPh, 4-FPh, 2-FPh, 2-NO2Ph, 2-OHPh, 4-MeOPh CH2Cl2 r.t., 81-93% N N O Me O 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 and for synthesis of 5-(2amino-5-aryl-1H -imidazol-4-yl)-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H ,3 H) -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 R Cl- , 2-PrOH, ∆ , h NH2 r.t., 24 h, 55-70% R O H2N + O N Me O O CO32-, NH2 H2N NH2 EtOH, AcOH, MW 150 °C, 10 min, 65-72% OH 127 h NH2 N Me O NH2 126 124 N N or OH H2N Me HO CO32- H ,∆ ,1 N NH O R NH2 2-PrOH, AcOH, 50 °C O Me O NH2 N O R = H, 4-MeO, 4-Cl, 4-Br, 4-NO2 N N Me 2Pr O Me NH2 Ac2O ∆ , 30 R NH2 O NH O O Me 128 N N N Me O Me N H OH 129 Scheme 49 The multicomponent condensation of guanidinium sulfate 130 with CH O 131 and H S 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 CH O and H S 77 NH S NH2 H2N NH2 SO42- + CH2O + H2S 131 70 ° C 132 S O S S S S S 130 N H N H H N H N S + S S O 134 (56 %) NH 133 (10 %) 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 NH HN CHO OHC NH + NH4OAc + O O O NH2 H2N 136 EtOH, AcOH NH N H r.t., 13 h 46 O 28% 135 O O 137 Scheme 51 Guanidine as a catalyst Guanidinium chloride 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 NH2 O + H R1 R2 NH2 H2N H N Cl R2 R3 + Me3SiCN R1 = t-Bu, Bn, n-pentyl, Ph, 4-ClPh, 2-furyl, R1 MeOH, 40 °C, 1h 82-98% 137 81 R2 = H, Et, Bn N R3 CN 138 R3 = Ph, Et, Bn 4-pyridyl, cinnamyl, i-propyl, 4-MeOPh Scheme 52 Guanidinium chloride 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 NH2 Cl O NH2 O NH2 H2N Me H O HN r.t., 3-4 h 80-90% R 42 139 R R = H, 4-Me, 4-F, 4-Cl, 4-NO2, 4-MeO 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 as catalyst (Scheme 54) They also used guanidinium chloride 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 R1 NH2 Cl O O R1 H Me O O OR2 NH4OAc 140, R2 = Me 96, R2 = Et NH2 H2N O R2O EtOH, r.t., h 95-98% OR2 N H 136 141 R1 = Ph, 4-ClPh, PhCH=CH, cyclohexyl, 2-Furyl, 4-MePh, 4-BrPh, 4-OHPh, 4-NO2Ph, n-pentyl Scheme 54 R1 NH2 Cl O O O R1 Me H H2N O NH4OAc OR2 O 136 140, R2 = Me 96, R2 = Et 142 NH2 15 O EtOH, r.t., h 75-95% O R2O N H 143 R1 = Ph, 4-ClPh, PhCH=CH, 2-Furyl, 4-MePh, 4-MeOPh, 4-OHPh, 4-NO2Ph, 3-pyridyl, 4-BrPh, n-Pr Scheme 55 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 Ar O R N H OH N + H C OH O 144 R = Me, CH2Ph O COOH + 145 H Ar (Me)2N OAc O N(Me)2 147 80 °C, 3-6 h 88-92% R N Ar Ar = Ph, 4-MePh, 4-MeOPh, 4-ClPh, 4-BrPh, 4-FPh, 3,4-(MeO)2Ph N O Ar OH 146 Scheme 56 368 NH2 H 148 CH3 RAHIMIFARD et al./Turk J Chem 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 References Wyss, P C.; Gerber, 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Using guanidine and its salt as reagent in multicomponent reactions usually leads to the formation of guanidinecontaining heterocycles, which are a very important class of therapeutic agents, and. .. 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... its salts from these points of view 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