Schmitzer, Andreea; University of Montreal, Chemistry; Is ... · Keywords: biguanide, superbase, ligand, organocatalyst Résumé. Dans cette minirevue nous discutons la chimie des

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The chemistry of biguanides: from synthetic routes to applications in organic chemistry

Journal: Canadian Journal of Chemistry

Manuscript ID cjc-2019-0371.R1

Manuscript Type: Mini Review

Date Submitted by the Author: 02-Dec-2019

Complete List of Authors: Fortun, Solène; University of Montreal, ChemistrySchmitzer, Andreea; University of Montreal, Chemistry;

Is the invited manuscript for consideration in a Special

Issue?:J Wuest

Keyword: biguanide, superbase, organocatalyst, ligand

https://mc06.manuscriptcentral.com/cjc-pubs

Canadian Journal of Chemistry

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The chemistry of biguanides: From synthetic routes to applications in organic chemistrySolène Fortuna and Andreea R. Schmitzer*a

a. Department of Chemistry, Faculty of Arts and Sciences, University of Montreal.

2900 Edouard Montpetit, CP 6128 Succursalle centre ville, H3C3J7 Montréal, Québec, Canada. *Corresponding

author: Prof. Andreea R. Schmitzer, Département de Chimie, Université de Montréal, tél. 514 343-6744,

[email protected]

Dedicated with respect to Professor James W. Wuest who developped biguanides chemistry and applied it for the exploration of organic materials during his internationally recognized research program.

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Abstract. In this mini-review, we discuss the chemistry of biguanides and their applications in catalysis. We present their super basicity as a consequence of their structure, the most efficient ways to synthesize symmetric and unsymmetric functionnalized biguanides and their applications in organic catalysis as triazine precursors and ligands in organo-metallic catalysis.

Keywords: biguanide, superbase, ligand, organocatalyst

Résumé. Dans cette minirevue nous discutons la chimie des biguanides et leurs applications en catalyse. Nous présentons la superbasicité de ces composés comme résultats direct de leur structure, les voies de synthèse les plus efficaces des biguanides symétriquement et non symétriquement fonctionnalisés, ainsi que leurs applications comme précurseurs de triazines et comme ligands en chimie organométallique.

Mots clé: biguanide, superbase, ligand, organocatalyseur

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IntroductionBiguanides are air-stable polynitrogenated compounds composed of two guanidine units bound by a common nitrogen atom (Fig. 1). They are polar and hydrophilic compounds, and therefore, highly soluble in aqueous media due to their chemical structure composed of two imino and three amino groups in tautomerism. X-ray diffraction (XRD) analysis and density functional theory (DFT) studies have shown that tautomer A without a hydrogen on the central bridging nitrogen atom has the highest stability amongst both neutral and HCl salts, due to the formation of an intramolecular H bond.1-3 As strong bases, biguanides are capable of chelating with protons as well as metal cations.4, 5 In this case, XRD shows that tautomer B is favored.6, 7 The strong interactions between the imino groups and metallic cation form a stable six-membered ring.

Fig. 1 The general structures of guanidine, biguanide and biguanide metal complex.

The first applications of biguanides were developed in the 1950’ due to their ability to interact with cellular membranes.8, 9 They were shown to have hypoglycemic,9, 10 antiseptic,11 and antimalarial12-14 properties, and have been studied for their anticancer effects over the past twenty years.15-17 Therefore, several biguanides have been developed as active pharmaceutical ingredients in a variety of readily available drugs. For example, metformin is an oral antidiabetic agent widely used as a treatment of type II diabetes, proguanil is an antimalarial drug and chlorhexidine has broad-spectrum antiseptic properties (Fig. 2). Subsequently, biguanides have been extensively studied for their anticancer effects, but their mechanism of action is still unknown and remains under investigation.

Fig. 2 Biguanides used as active pharmaceutical ingredients in a variety of readily available drugs.

This mini-review provides a summary of the chemical properties of biguanides, followed by an extensive description of the synthetic routes used in their preparation. Their applications in organic chemistry as triazine precursors, bases and ligands for organometallic catalysis are then discussed.

Chemical propertiesExtreme basicity

A strong base is a chemical compound with a high affinity for protons, which completely dissociates water and which conjugated acid has a high acidity constant (pKa >14). However, there is no generally accepted definition for the term “superbase” reported in the literature. In 1993, Paul Caubère explained that the term “superbase” does not mean a base that is thermodynamically and/or kinetically stronger than another. Instead, it means that a basic reagent is created by combining the characteristics of several different bases. A superbase may be more efficient than its component bases in some reactions and less efficient in others.18 It is therefore not associated with a specific pKa value, but with a specific chemical structure.Biguanides are strong bases (stronger than guanidine) because protons have a high affinity with biguanide due to the formation of a bidentate hydrogen bond, which stabilizes the protonated base (Fig. 3).19 A protonated biguanide possesses different resonance forms. Biguanides also belong to the family of organo-superbases since they combine two guanidines, themselves being a combination of three amines (Fig. 4).3, 20 DFT calculations have also shown that the strong n-π conjugation between the amino and imino groups results in the exceptional basicity of the imino groups in biguanides.5 Subsequently, protonation occurs on the imino groups rather than on the amino groups.

Fig. 3 Protonated biguanide and its resonance forms.

Fig. 4 The structures and acidity constants of the conjugated acids of methylamine, guanidine and biguanide.21

Biguanides are usually reported as mono- or dihydrochloride salts and therefore possess two acidity constants: pKa1 ≈ 10-18 and pKa2 ≈ 2-4 (Fig. 5).21 It is interesting to note that Raman scattering and DFT studies on metformin have shown that its neutral form (Big) does not dominate even at pH >13, while its diprotonated form (Big2+) is the major species at pH <1.5.3 The number of protons is determined by acid-base titration, elemental analysis and 1H NMR analysis as the NH protons of the mono-protonated salts give well resolved peaks in the range of 5-9 ppm. The protonation state also influences the shielding of the carbon atoms in 13C NMR spectroscopy.22 The carbon peaks of neutral biguanides are observed around 158-162 ppm, while the carbon atoms bound to a

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protonated nitrogen atom appear around 152-155 ppm. The protonation of biguanides limits the proton exchange in the molecule and the electronic density is more localized, shielding the carbon atoms.

Fig. 5 Structures of the protonated forms of biguanide.

Geometry

Biguanides are composed of two guanidine units (showed in red and blue in Fig.5) that share a common N atom. Raczynska et al. performed DFT calculations and proposed that the two guanidine units of a neutral biguanide are almost planar due to the formation of an intramolecular hydrogen bond.5 However, LeBel et al. showed by XRD studies that the plans containing the two guanidines are forming a 15° dihedral angle.23 They also showed that mono- and di-protonated biguanides are twisted by 24 and 28° in the solid state and form a “corrugated ribbon”, each molecule donating two hydrogen bonds with one neighbor and accepting two hydrogen bonds form another.

Synthesis of the biguanidesSimple biguanides are polar and hydrophilic compounds and therefore, highly soluble in aqueous media. The addition of apolar aryl or alkyl groups provides lipophilic properties and gives access to a wide range of compounds with numerous properties. For example, it is possible to create supramolecular assemblies with π-stacking interactions or form micelles with amphiphilic biguanides. Even though every nitrogen atom (except the central one) can carry functional groups, biguanides are usually mono- or disubstituted at both ends at positions N1 and/or N5 (Fig. 6).

Fig. 6 Biguanide substituted at both ends and numbering of its nitrogen atoms.

Three main routes have been developed to synthesize biguanides depending on their nature and degree of substitution (Fig. 7). The first route consists of preparing symmetric biguanides from sodium dicyanoazanide and two equivalents of a primary or secondary amine in the presence of hydrochloric acid. The second route consists of preparing symmetric and unsymmetric biguanides from a cyanoguanidine compound and one equivalent of a primary or secondary amine under a variety of different reaction conditions. The last route consists of synthesizing highly substituted unsymmetric biguanides from a guanidine compound and carbodiimide. Finally, there are also a number of synthetic approaches to functionalize biguanides.

Fig. 7 The main synthetic routes used to prepare biguanides.

Synthesis of symmetric biguanides from sodium dicyanoazanide

Symmetric biguanides are readily obtained in environmentally friendly solvents upon the addition of two equivalents of a primary or secondary amine to one equivalent of sodium dicyanoazanide (Fig. 7–1). In 2005, LeBel et al. reported the synthesis of a variety of diphenylbiguanides in moderate to good yield depending on the nature of the aniline substituents (Fig. 8–1).23 In 2014, Pai et al. synthesized diisopropylbiguanide in moderate yield (68%) (Fig. 8–2).24 Biguanide polymers, such as poly(alkylene biguanides), have also been synthesized using this method.25

Fig. 8 Synthesis of symmetric biguanides from sodium dicyanoazanide.

Synthesis of unsymmetric biguanides from functionalized cyanoguanidinesA large variety of unsymmetric biguanides can be obtained upon the reaction of a primary or secondary amine with a cyanoguanidine compound. (Fig. 7-2). This reaction requires acidic conditions to protonate the nitrile group in the cyanoguanidine and activate the nucleophilic attack of the amine, otherwise the reaction is too slow to take place.26 Hydrochloric acid is usually used and the ideal pH of the reaction media is 2.6. Some research groups have replaced this proton source with other activating agents such as FeCl3 and TMSCl (see below).Substituted cyanoguanidines are easily obtained from the previous method using only one equivalent of primary or secondary amine. In 2013 and 2015, Gräber et al. and Prati et al. reported the synthesis of alkylbis-cyanoguanidines (Fig. 9–1) and three alkyl- or aryl-cyanoguanidines (Fig. 9–2)), respectively.27, 28 They both use amine hydrochloride salts in 1-butanol under reflux conditions. The substituted cyanoguanidines were obtained in moderate to excellent yields.

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Fig. 9 Synthesis of substituted cyanoguanidines from sodium dicyanoazanide.

In 1989, Suyama et al. developed a very efficient route to synthesize a large number of substituted biguanides.29 They used iron(III) chloride as a Lewis acid to increase the reactivity of cyanoguanidine. Iron(III) chloride reacts in a stoichiometric amount, and moderate to excellent yields were obtained (55–99%) (Fig. 10). However, only alkyl and aryl groups were used in the reaction, probably because iron coordinates with other functional groups (such as alcohols, ethers and halogens), which prevents the formation of the biguanide or decrease its yield.

Fig. 10 Synthesis of biguanides from cyanoguanidines in the presence of iron(III) chloride.

In 2004, Mayer et al. developed a synthetic route utilizing microwave irradiation reacting substituted anilines or benzylamines with commercially available and inexpensive 1-cyanoguanidine (also known as dicyandiamide) (Fig. 11).30 This method is versatile and tolerant toward a wide range of functional groups (alkyl, ether, halogen, nitro and ester groups) and solvents (water, alcohols, toluene, 1,4-dioxane, THF, acetone, and acetonitrile). The authors optimized the reaction conditions in acidic medium using hydrochloric acid, but they discovered afterwards that the yield and purity of the reaction increased when HCl was replaced with trimethylsilyl chloride. The reaction became more tolerant to new functional groups, such as additional amines, alcohols, and carboxylic acids.

Fig. 11 Synthesis of biguanides synthesis from 1-cyanoguanidine using microwave irradiation.

Finally, different research groups have reported the synthesis of biguanides in environmentally friendly organic solvents under reflux conditions in the presence of hydrochloric acid (Fig. 12). In 2005, LeBel et al. synthesized 1-phenylbiguanide hydrochloride, 1,3- and 1,4- phenylenebis-biguanide dihydrochloride in refluxing aqueous HCl (1 M) in 84, 51, and 61% yield, respectively after 12 h.23 In 2013, Gräber et al. used the previously described cyanoguanidine compounds (Fig. 9–1) to synthesize a variety of alkylbis-biguanide dihydrochloride compounds.27 They used 1-butanol to reach higher temperatures and performed the reactions in a shorter time (6 h). The yields varied depending on the nature of the reactants substituents.

Fig. 12 Synthesis of biguanides from cyanoguanidines under reflux conditions in the presence of hydrochloric acid.

Synthesis of highly substituted unsymmetric biguanides from guanidinesUnsymmetric biguanides possess three substituted nitrogen atoms. In 1998, Pr. Gelbard’s group was the first to report the synthesis of heptasubstituted biguanides from tetramethylguanidine and a carbodiimide compound (Fig. 13).31 Although the reaction conditions were not described in detail, the authors specified that the addition of guanidine to the carbodiimide was performed upon heating the reactants in a polar and protic solvent, and that DMF was more suitable than THF. Several research groups have recently optimized this method using solvent-free conditions under microwave irradiation or reflux conditions in butanol.32

Fig. 13 Synthesis of unsymmetric biguanides upon the addition of tetramethylguanidine to a functionalized carbodiimide compound.

Functionalized biguanidesAlizadeh and Veisi envisaged the use of biguanides in organometallic catalysis and developed the functionalization of metformin via a nucleophilic substitution reaction at the N1 position. They mainly used insoluble bulky functional groups, such as functionalized silicas, carbon nanotubes, and fullerenes. In general, the reactions were performed in the presence of a base and metformin was used in the form of its hydrochloride salt or free base. Unfortunately, the yields were not reported.In 2012, Alizadeh et al. added metformin onto two different types of functionalized silica via a nucleophilic substitution reaction in the presence of K2CO3 or NaOH in acetonitrile under reflux conditions (Fig. 14).33, 34 A catalytic amount of potassium iodide was added to favor the nucleophilic substitution reaction.

Fig. 14 Functionalization of metformin using functionalized silicas.

Later in 2013, Veisi et al. reported the aromatic nucleophilic substitution of a triazine compound using metformin hydrochloride in acetonitrile under reflux conditions in the presence of N,N-diisopropylethylamine (Fig. 15).35

Fig. 15 Functionalization of metformin using a triazine compound.

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In 2014, Veisi et al. continued their study and functionalized metformin with carbon nanotubes and then fullerene C60 using a nucleophilic substitution reaction of a variety of aryl chlorides. The reactions were performed in the presence of a base (NaH or triethylamine) in DMF at high temperature (reflux or 120 °C) (Fig. 16).36, 37 The authors specified that a metformin:aryl chloride ratio of 10:1 (by mass) was used.

Fig. 16 Functionalization of metformin via the nucleophilic substitution of an acyl chloride.

In 2015, Zhang et al. explored the functionalization of biguanides via a C-N cross-coupling reaction. They were inspired by the Ullmann coupling to develop a copper-catalyzed arylation of metformin.38 After extensive optimization of the reaction temperature, solvent, base, ligand, and copper salt, the arylation of metformin was performed in THF at 80 °C for 12 h in the presence of K3PO4 (Fig. 17). Only aryl iodides gave the desired product under these reaction conditions. In order to use bromide or aryl chloride reactants, the reaction had to be carried out in 1,4-dioxane at 110 °C and the base was replaced with K2CO3. The desired products were obtained in various yields depending on the nature of functional groups in the aromatic substrate.

Fig. 17 Copper-catalyzed arylation of metformin.

Applications in organic chemistrySuperbases in organo-catalysis

Some research groups used biguanides in organo-catalysis as organo-superbase because they are soluble in organic solvents with a pKa similar to inorganic bases’. Biguanides were then used in many organic reactions such as vegetal oils transesterification,31, 39,

40 aldol condensation,34 Henry33, 34, 41 and Michael reactions.34

Triazine precursors

The main application of biguanides in organic synthesis is their use as precursors in the synthesis of 2,4-diamino-1,3,5-triazine derivatives (Fig. 18). Triazine derivatives are bioactive molecules commonly used as neuronal blockers,42 enzyme inhibitors28, 43 and anticancer drugs.44, 45 These heterocyclic compounds are also very useful in supramolecular chemistry due to their ability to form multiple hydrogen bonds (Fig. 18).46 For example, they are able to self-assemble and induce crystallization.47-49

Fig. 18 General structure of 1) a 2,4-diamino-1,3,5-triazine derivative and 2) the hydrogen bond network formed by triazines.

Four synthetic routes are mainly used to obtain triazines from biguanides (Fig. 19). The first two consist of the condensation of acetone or an ester with the imine groups of the biguanide (Fig. 19-1),42 whereas the reaction with esters is performed on biguanides containing various functional groups (Fig. 19–2)).42, 43, 50 Finally, two catalytic reactions have been reported by Pr. Zhang’s group. In 2016 they reported the condensation of a variety of benzylic alcohols with a biguanide catalyzed by a ruthenium complex (Figure 19–3)51 and in 2017, the double insertion of imines on a gem-dibrominated alkene catalyzed by a copper complex (Fig. 19–4).52 The triazines derivatives were obtained in various yields depending on the nature of the reactants functional groups.

Fig. 19 Synthesis of triazines synthesis from biguanides.

Ligands in organometallic catalysis

Biguanides are air-stable compounds, which can be used as N-donor ligands in organometallic catalysis. They stabilize metallic nanoparticles via N-chelation, preventing their aggregation and therefore their deactivation. In addition, they can act as bidentate ligands via the two imino groups and offer a greater stability to metal complexes than monodentate ligands. Ray et al. reported the coordination properties of biguanides to various metals in early 1961,4, 53 however, it is only in the last decade that Alizadeh, Veisi, and Schmitzer explored their use as ligands in organometallic catalysis (Table 1). The Suzuki-Miyaura cross-coupling reaction has been widely studied using several ligands in environmentally friendly solvents and short reaction times (Table 1, entries 1–8). In 2013, Alizadeh et al. demonstrated the interesting role of metformin as a ligand with the desired coupling product being obtained in 98% yield after only 30 min at 80 °C using a water:ethanol (1:1) mixture in the presence of 1 mol% Pd. (Table 1, entry 1).54 Larger assemblies containing a metallic biguanide complex were then studied by Alizadeh and Veisi including functionalized silicas (Fig. 20–1 and 20–2; Table 1, entries 2–3),55, 56 carbon nanotubes (Fig. 20–3; Table 1, entry 4),36 and fullerene C60 (Fig. 20–4; Table 1, entry 5).37 Catalyst 1 was used at 0.14 mol%, whereas catalysts 2, 3, and 4 were used at 1 mol%. As insoluble compounds, they were all recycled 5–6 times via centrifugation and/or filtration. All these catalytic

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systems were studied in a water:ethanol (1:1) mixture at different temperatures (from rt to 80 °C). Despite the solvent and the low temperatures used, these catalytic systems cannot be considered environmentally friendly because the large assemblies do not respect the principles of atom economy, and carbon nanotubes and fullerene are highly toxic. In 2016, Veisi et al. functionalized chitosan with a biguanide Pd complex (Fig. 20–5) and performed an efficient Suzuki–Miyaura coupling with only 0.15 mol% Pd in 2 h at 40 °C in a water:ethanol (1:1) mixture (Table 1, entry 6).57 The aqueous phase containing the soluble catalyst 5 was recycled after extraction of the organic products. This catalytic system was recycled 7 times at 0.75 mol% Pd.Ethanol is considered a good solvent in term of environmental concerns, but is highly flammable.58 Therefore, Schmitzer et al. studied biguanide-based catalytic systems in neat water to reduce the risk of accident if used in industry. In 2017, Schmitzer et al. preformed the Pd:metformin (1:1) complex in situ in neat water and obtained the Suzuki–Miyaura coupling product in 95% yield in the presence of 2.5 10-3 mol% Pd in 15 min at 100 °C (Table 1, entry 7).59 The aqueous phase containing the catalytic species was recycled 4 times at 0.5 mol% Pd. In 2018, a biguanide-based surfactant, hexylbiguanide was used in the same Suzuki–Miyaura coupling reaction under micellar conditions. The desired product was obtained in 98% yield in the presence of 0.5 mol% Pd in 15 min at 100 °C and the catalytic species were recycled 6 times (Table 1, entry 8).60

Biguanide metal complexes were also used as efficient ligands in the Heck and Ullman cross-coupling reactions (Table 1, entries 9 and 10),35, 61 the N-arylation of indoles and imidazoles, and the O-arylation reaction of phenols (Table 1, entries 11–14).62-64

Table 1 A summary of the reactions catalyzed by biguanide metal complexes.

Fig. 20 Assemblies containing biguanide metal catalysts.

ConclusionsIt is surprising that biguanides have not yet found more extensive use as bidentate ligands in organometallic catalysis. Their polarity, water-solubility, and non-toxicity are important properties that may result in interesting applications in environmentally friendly catalytic processes. The large choice of commercially available amines and synthetic methods used to prepare biguanides allows the development of virtually any designed biguanide. Biguanides are electron-rich and air-stable compounds, they exhibit interesting metal coordination properties due to their nitrogen atoms that can stabilize metal nanoparticles, but the stability of metal-biguanide complexes has yet to be demonstrated. This mini-review may encourage researchers to think about the biguanides exploitable properties and their potential use in catalysis or material sciences.

Conflicts of interestThere are no conflicts to declare.

AcknowledgementsWe gratefully acknowledge the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Université de Montréal for financial support (ARS is the PI for NSERC grant 03866).

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392.54. Alizadeh, A.; Khodaei, M. M.; Kordestani, D.; Beygzadeh, M. Tetrahedron Lett. 2013, 54, 291.55. Beygzadeh, M.; Alizadeh, A.; Khodaei, M. M.; D. Kordestani, Catal. Commun. 2013, 32, 86.56. Veisi, H.; Kordestani, D.; Hemmati, S.; Faraji, A. R.; Veisi, H. Tetrahedron Letters, 2014, 55, 5311.57. Veisi, H.; Ghadermazi, M.; Naderi, A. Appl. Organomet. Chem. 2016, 30, 341.58. Prat, D.; Wells, A.; Hayler, J.; Sneddon, H.; McElroy, C. R.; Abou-Shehada, S.; Dunn, P. J. Green Chem. 2016, 18, 288.59. Fortun, S.; Beauclair, P.; Schmitzer, A. R. RSC Adv. 2017, 7, 21036.60. Fortun, S.; Schmitzer, A. R. ACS Omega 2018, 3, 1889.61. Zhang, C.; Zhan, Z.; Lei, M.; Hu, L. Tetrahedron 2014, 70, 8817.62. Veisi, H.; Morakabati, N. New J. Chem. 2015, 39, 2901.63. Ghorbani-Vaghei, R.; Hemmati, S.; Veisi, H. Tetrahedron Lett. 2013, 54, 7095.64. Akhavan, E.; Hemmati, S.; Hekmati, M.; Veisi, H. New J. Chem. 2018, 42, 2782.

Page 8 of 21



Draft

REVIEW



Tables

Table 1 A summary of the reactions catalyzed by biguanide metal complexes.

Entry Reaction Catalytic species (mol%)Reaction

conditionsa Catalytic runs

154 Suzuki–MiyauraPd(OAc)2 (1 mol%)

Metformin (2 mol%)EtOH:H2O (1:1)80 °C, 30 min

–

255 Suzuki–Miyaura 1 (0,14 mol%)EtOH:H2O (1:1)

80 °C, 1 h5

356 Suzuki–Miyaura 2 (1 mol%)EtOH:H2O (1:1)50 °C, 35 min

7

436 Suzuki–Miyaura 3 (1 mol%)EtOH:H2O (1:1)50 °C, 30 min

5

537 Suzuki–Miyaura 4 (1 mol%)EtOH:H2O (1:1)

rt, 180 min6

657 Suzuki–Miyaura 5 (0.15 mol%)EtOH:H2O (1:1)

40 °C, 2 h7

(at 0.75 mol% Pd)

759 Suzuki–MiyauraPd(OAc)2 (2.5 10–3 mol%)

Metformin (2.5 10-3 mol%)H2O

100 °C, 15 min4

(at 0.5 mol% Pd)

860 Suzuki–MiyauraPd(OAc)2 (0.5 mol%)

Hexylbiguanide (0.5 mol%)H2O

100 °C, 15 min6

935 Heck 2 (1 mol%)DMF

Reflux, 3 min5

1061 UllmannCuI (10 mol%)

Metformin (20 mol%)EtOH

Reflux, 1 h–

1163 Imidazole N-arylationCuI (5 mol%)

Metformin (10 mol%)DMF

110 °C, 15 h–

1262 Indoles and imidazoles N-arylation

3 (0.2 mol%)DMF

110 °C, 6–10 h5

1363 Phenol O-arylationCuI (10 mol%)

Metformin (10 mol%)Acetonitrile

60 °C, 8 h-

1464 Indoles N-arylationPhenol O-arylation

6 (1.3 mol%)DMF

80 °C, 3 h8

(for the N-arylation)

a Optimized reaction conditions leading to yields >90 %.

Figure captions

Figure 1. The general structures of guanidine, biguanide and biguanide metal complex.

Figure 2. Biguanides used as active pharmaceutical ingredients in a variety of readily available drugs.

Figure 3. Protonated biguanide and its resonance forms.

Figure 4. The structures and acidity constants of the conjugated acids of methylamine, guanidine and biguanide.21

Figure 5. Structures of the protonated forms of biguanide.

Figure 6. Biguanide substituted at both ends and numbering of its nitrogen atoms.

Figure 7. The main synthetic routes used to prepare biguanides.

Page 9 of 21



Draft


10 | J. Name., 2019, 00, 1-3



Figure 8. Synthesis of symmetric biguanides from sodium dicyanoazanide.

Figure 9. Synthesis of substituted cyanoguanidines from sodium dicyanoazanide.

Figure 10. Synthesis of biguanides from cyanoguanidines in the presence of iron(III) chloride.

Figure 11. Synthesis of biguanides synthesis from 1-cyanoguanidine using microwave irradiation.

Figure 12. Synthesis of biguanides from cyanoguanidines under reflux conditions in the presence of hydrochloric acid.

Figure 13. Synthesis of unsymmetric biguanides upon the addition of tetramethylguanidine to a functionalized carbodiimide

compound.

Figure 14. Functionalization of metformin using functionalized silicas.

Figure 15. Functionalization of metformin using a triazine compound.

Figure 16. Functionalization of metformin via the nucleophilic substitution of an acyl chloride.

Figure 17. Copper-catalyzed arylation of metformin.

Figure 18. General structure of 1) a 2,4-diamino-1,3,5-triazine derivative and 2) the hydrogen bond network formed by triazines.

Figure 19. Synthesis of triazines synthesis from biguanides.

Figure 20. Assemblies containing biguanide metal catalysts.

Page 10 of 21



Draft

N N

NR1

N

NR6

R2 R5

Biguanide

R1 - R6 = H, alkyl, benzyl, arylM = metal cation

R3 R4

N N

NR1

R2

Guanidine

R5

R4

R3

N NH

NR1

N

NR6

R2 R5

R3 R4

A B

N NH

NR1

N

NR6

R2 R5

R3 R4M

Biguanide metal complex

H

Figure 1. The general structures of guanidine, biguanide and biguanide metal complex.

H2N N

NH

N

NH2

Metformin

NH

N

NH2

NH

NHCl

HNN

HN

NHNH2

Cl

Chlorhexidine

HNN

HN

NH2NH

Proguanil

Cl

Figure 2. Biguanides used as active pharmaceutical ingredients in a variety of readily available drugs.

Page 11 of 21



Draft

H2N N

NH

NH2

NH2 H+

H2N N

NH2

NH2

NH2

H2N N

NH2

NH2

NH2

H2N N

NH2

NH2

NH2

H2N N

NH2

NH2

NH2

H2N N

HN

NH2

NH2

H

Figure 3. Protonated biguanide and its resonance forms.

NH2H2N

NH

NH2H2N

NH

N

NH2

NH2

MethylaminepKa = 10.66

GuanidinepKa = 13.60

DimethyliguanidepKa = 13.85

Figure 4. The structures and acidity constants of the conjugated acids of methylamine, guanidine and biguanide.21

Page 12 of 21



Draft

R1 - R6 = H, alkyl, benzyl, aryl

H+

N N

NH+

R1N

NHR6

R2 R5

R3

H+

N NH

NH+

R1N

NH+

R6

R2 R5

R3 R4

pKa2 = 2 - 4pKa1 = 10 - 18

Big+ Big2+Big

R4

N N

NR1

N

HNR6

R2 R5

R3R4

Figure 5. Structures of the protonated forms of biguanide.

N1 N3H

N2HR1

N5

N4HR4

R2 R3

R1 - R4 = H, alkyl, aryl, benzyl, etc.

Figure 6. Biguanide substituted at both ends and numbering of its nitrogen atoms.

Page 13 of 21



Draft

NNa

N+ HN

R1

R2NH

N

NHR1

NH

NR2

R1N HCl2

R2

NH

N

NHR3

R4

N

1)

2) + HNR1

R2NH

N

NHR3

NH

NR2

R1

R4

N N

NHR4

+ N NH

N NH

NR6

R5

R1 R1

R2 R3

R5 N C N R6

R2

R3 R4

3)

HCl

HCl

HCl

Figure 7. The main synthetic routes used to prepare biguanides.

Page 14 of 21



Draft

NNa

N+ N

HNH

NH NH

NH

N2

HClaq 1 M

Reflux, 12 h

NNa

N+ N

HNH

NH NH

NH

N2

HCl

2-Butanol, pH 2-3

Reflux, 70 h

68 %

1)

2)

NH2R

R R

R = H, 70 %R = CH3, 49 to 71 %R = 4-OCH3, 60 %R = 4-CN, 68 %

R = Br, 54 to 63 %R = 3,5-CH3, 68 %R = 2,4,6-CH3, 69 %

HCl

NH2

HCl

Figure 8. Synthesis of symmetric biguanides from sodium dicyanoazanide.

NNa

N+

N

2 HCl

1-Butanol

Reflux, 8-18 h

n = 2, 99 %n = 4, 50 %n = 6, 80 %

NNa

N+ H2N

NH

NH

NHN

HCl

N1-Butanol

Reflux, 6 hR R

R = CH2CH3, 73 %R = (CH2)2CH3, 63 %R = Ph, 100 %

H2N NH2nNH nN

H

NH

NH

NH

NHN N

1)

2)

Figure 9. Synthesis of substituted cyanoguanidines s from sodium dicyanoazanide.

Page 15 of 21



Draft

NH

R3NH

NHCN + + FeCl3

1,4-Dioxane or THF

R. T. or reflux NH

R3NH

NH NH

NR1

R2

R1, R2 = H, alkyl, Ph, BnR3 = H, Ph

n = 1, 2

HNR1

R2

n HCl

Figure 10. Synthesis of biguanides from cyanoguanidines in the presence of iron(III) chloride.

H2N NH

NHCN +

HCl or TMSCl (1 to 2 eq.)

CH3CNMW, 150 to 170 °C, 10 to 15 min

H2N NH

NH NH

NH

NH2n

n = 0, 1R = alkyl, aryl, halogen,

OH, OCH3,NH2, NO2, COOH

nR RHCl

Figure 11. Synthesis of biguanides synthesis from 1-cyanoguanidine using microwave irradiation.

Page 16 of 21



Draft

NH

NH

NHCN +

HCl

Solvent, reflux NH

NH

NH NH

NR1

R1 - R3 = alkyl, aryl, benzyl

HNR1

R2R2

R3 R3

HCl

1-Phenylbiguanide

HN

HN NH2

NH NH

HCl

1,3-Phenylenebis-biguanide 1,4-Phenylenebis-biguanide

HN

HN

H2N

NH

NHNH

NH

HN

NH2HN

HNHN

NHNH

NH2NHH2NNH

HNHN

2 HCl 2 HCl

NH

NH

NH

NH

NH

NH NH NH

NH

NH

n

2 HCl

Alkylbis-biguanide

n = 2, 4, 6R = alkyl, aryl

R R

Figure 12. Synthesis of biguanides from cyanoguanidines under reflux conditions in the presence of hydrochloric acid.

N N

NH+ N N

H

N NH

NR

R = iPr, 62 %R = Cy, 94 %

R

R N C N R

Figure 13. Synthesis of unsymmetric biguanides upon the addition of tetramethylguanidine to a functionalized carbodiimide compound.

Page 17 of 21



Draft

silica Cl +Base, KI

Acetonitrile, reflux silica NH

NH

NH

N

NH

H2N NH

NH

N

NH

HCl

Figure 14. Functionalization of metformin using functionalized silicas.

+DIEA

CH3CN, refluxH2N NH

NH

N

NH

HCl

N

NN

Cl

Cl

HNN

NN

HN

HN

HN

silica silicaNH

HNN

NH

NH

HNNH

N

Figure 15. Functionalization of metformin using a triazine compound.

ClR +Base

DMF NH

NH

NH

N

NH

H2N NH

NH

N

NH

HCl

O

R

O

R = nanotubes de carbone, fullerène C60

Figure 16. Functionalization of metformin via the nucleophilic substitution of an acyl chloride.

RI + H2N N

H

NH

N

NH

HCl

10 mol% CuI20 mol% ligand

K3PO4

THF, 12 h, 80 °C NH

NH

NH

N

NH

R

Ligand:N N

R = H, 86 %R = p-OCH3, 90 %R = p-CN, 94 %R = p-NO2, 40 %R = Br, Cl, F, 70 à 82 %

Figure 17. Copper-catalyzed arylation of metformin.

Page 18 of 21



Draft

N

N

N

N NR5R2

R3 R4

R1

2,4-Diamino-1,3,5-triazine derivatives

R1 - R5 = H, alkyl, aryl, halogen, OH, etc.

N

N

N

N NHH

H H

H

HNH2N

N

N

N

H

HNH2N

N

N

N

N

N

N

H2N NH2

1) 2)

Figure 18. General structure of 1) a 2,4-diamino-1,3,5-triazine derivative and 2) the hydrogen bond network formed by triazines.

Page 19 of 21



Draft

NH

NH

NH2

NHNH

+O

NH

NH

NH2

NN

NH

NH

NH2

NHNHR1 +

NH

NH

NH2

NNR1

R2O

OEt

2,2-DimethoxypropaneHClconc

MeOH, reflux

32 to 48 %

MeONa, MeOHor EtONa, EtOH

16 to 76 %

RR

R1 = aryl, functionalized5- or 6-membered rings

R2 = CH3, CH2Cl, CN, OH, Br

1)

2)

R = H, p-Cl, p-CH3,p-CH3OH, m,p-diCl

R2

3)

4)

R1 à R4 = H, CH3, Ar,5- or 6-membered rings

+ NR2

R1NH

NH

NH

N

HCl

RuCl2(COD) 2 mol%

t-BuOK1,4-Dioxane, 100 °C

NR2

R1N

NH

N

N

Ar

Ar OH R4

R3R4

R3

Br

BrAr +

CuI 10 mol%Bidentate ligand 20 mol%

K3PO41,4-Dioxane, 110 °C, 12 h

NR2

R1N

NH

N

N

Ar

NR2

R1NH

NH

NH

N

HCl

R4

R3 R4

R3

R1 à R4 = H, CH3, Ar,5- or 6-membered rings

Figure 19. Synthesis of triazines synthesis from biguanides.

Page 20 of 21



Draft

SiHN

HN N

HN NHPd

AcO OAc

OOO

SiO2

Fe3O4

1Magnetic iron nanoparticules silica

Si

NH

O O O

NN

NHN

HN NHN N

H

NH

NH

N

NH

HN

Si

HN

OOO

N N

N NH

NHHNNN

H

HN

HN

N

NH

NH

O

OH OH OH

SBA-15/CCMet/Pd(II)

2SBA-15 silica

Pd0

Pd0

Pd0

Pd0

NH

O

NH N

NHHNHN

HN

ONH

N

HN

3Single-walled carbon nanotube

Pd0

Pd0

NH

O

NH

N

HN NHPd0

4C60 fullerene

OHO

NHO

OH

NH

NH2

HN

NH

Pd0

n

5Chitosan

NH

O

NH N

NHHN

6Multi-walled carbon nanotube

CuCl

O

NH

NH

HNN

NHCuCl

Figure 20. Assemblies containing biguanide metal catalysts.

Page 21 of 21



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Schmitzer, Andreea; University of Montreal, Chemistry; Is ... · Keywords: biguanide, superbase, ligand, organocatalyst Résumé. Dans cette minirevue nous discutons la chimie des