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Search for "biguanide" in Full Text gives 3 result(s) in Beilstein Journal of Organic Chemistry.
Synthetic accesses to biguanide compounds
- Oleksandr Grytsai,
- Cyril Ronco and
- Rachid Benhida
Beilstein J. Org. Chem. 2021, 17, 1001–1040, doi:10.3762/bjoc.17.82
- Oleksandr Grytsai Cyril Ronco Rachid Benhida Institut de Chimie de Nice UMR7272, Parc Valrose, Université Côte d’Azur, Nice, France Department of Chemical and Biochemical Sciences, Mohammed VI Polytechnic University (UM6P), Ben Guerir, Morocco 10.3762/bjoc.17.82 Abstract Biguanide is a unique
- standard disinfectant and antiseptic. Although scarcely represented, the number of “success stories” with biguanide-containing compounds highlights their value and their unexploited potential as future drugs in various therapeutic fields or as efficient metal ligands. This review provides an extensive and
- critical overview of the synthetic accesses to biguanide compounds, as well as their comparative advantages and limitations. It also underlines the need of developing new synthetic methodologies to reach a wider variety of biguanides and to overcome the underrepresentation of these compounds. Keywords
Graphical Abstract
Figure 1: Tautomeric forms of biguanide.
Figure 2: Illustrations of neutral, monoprotonated, and diprotonated structures biguanide.
Figure 3: The main approaches for the synthesis of biguanides. The core structure is obtained via the additio...
Scheme 1: The three main preparations of biguanides from cyanoguanidine.
Scheme 2: Synthesis of butylbiguanide using CuCl2 [16].
Scheme 3: Synthesis of biguanides by the direct fusion of cyanoguanidine and amine hydrochlorides [17,18].
Scheme 4: Synthesis of ethylbiguanide and phenylbiguanide as reported by Smolka and Friedreich [14].
Scheme 5: Synthesis of arylbiguanides through the reaction of cyanoguanidine with anilines in water [19].
Scheme 6: Synthesis of aryl- and alkylbiguanides by adaptations of Cohn’s procedure [20,21].
Scheme 7: Microwave-assisted synthesis of N1-aryl and -dialkylbiguanides [22,23].
Scheme 8: Synthesis of aryl- and alkylbiguanides by trimethylsilyl activation [24,26].
Scheme 9: Synthesis of phenformin analogs by TMSOTf activation [27].
Scheme 10: Synthesis of N1-(1,2,4-triazolyl)biguanides [28].
Scheme 11: Synthesis of 2-guanidinobenzazoles by addition of ortho-substituted anilines to cyanoguanidine [30,32] and...
Scheme 12: Synthesis of 2,4-diaminoquinazolines by the addition of 2-cyanoaniline to cyanoguanidine and from 3...
Scheme 13: Reactions of anthranilic acid and 2-mercaptobenzoic acid with cyanoguanidine [24,36,37].
Scheme 14: Synthesis of disubstituted biguanides with Cu(II) salts [38].
Scheme 15: Synthesis of an N1,N2,N5-trisubstituted biguanide by fusion of an amine hydrochloride and 2-cyano-1...
Scheme 16: Synthesis of N1,N5-disubstituted biguanides by the addition of anilines to cyanoguanidine derivativ...
Scheme 17: Microwave-assisted additions of piperazine and aniline hydrochloride to substituted cyanoguanidines ...
Scheme 18: Synthesis of N1,N5-alkyl-substituted biguanides by TMSOTf activation [27].
Scheme 19: Additions of oxoamines hydrochlorides to dimethylcyanoguanidine [49].
Scheme 20: Unexpected cyclization of pyridylcyanoguanidines under acidic conditions [50].
Scheme 21: Example of industrial synthesis of chlorhexidine [51].
Scheme 22: Synthesis of symmetrical N1,N5-diarylbiguanides from sodium dicyanamide [52,53].
Scheme 23: Synthesis of symmetrical N1,N5-dialkylbiguanides from sodium dicyanamide [54-56].
Scheme 24: Stepwise synthesis of unsymmetrical N1,N5-trisubstituted biguanides from sodium dicyanamide [57].
Scheme 25: Examples for the synthesis of unsymmetrical biguanides [58].
Scheme 26: Examples for the synthesis of an 1,3-diaminobenzoquinazoline derivative by the SEAr cyclization of ...
Scheme 27: Major isomers formed by the SEAr cyclization of symmetric biguanides derived from 2- and 3-aminophe...
Scheme 28: Lewis acid-catalyzed synthesis of 8H-pyrrolo[3,2-g]quinazoline-2,4-diamine [63].
Scheme 29: Synthesis of [1,2,4]oxadiazoles by the addition of hydroxylamine to dicyanamide [49,64].
Scheme 30: Principle of “bisamidine transfer” and analogy between the reactions with N-amidinopyrazole and N-a...
Scheme 31: Representative syntheses of N-amidino-amidinopyrazole hydrochloride [68,69].
Scheme 32: First examples of biguanide syntheses using N-amidino-amidinopyrazole [66].
Scheme 33: Example of “biguanidylation” of a hydrazide substrate [70].
Scheme 34: Example for the synthesis of biguanides using S-methylguanylisothiouronium iodide as “bisamidine tr...
Scheme 35: Synthesis of N-substituted N1-cyano-S-methylisothiourea precursors.
Scheme 36: Addition routes on N1-cyano-S-methylisothioureas.
Scheme 37: Synthesis of an hydroxybiguanidine from N1-cyano-S-methylisothiourea [77].
Scheme 38: Synthesis of an N1,N2,N3,N4,N5-pentaarylbiguanide from the corresponding triarylguanidine and carbo...
Scheme 39: Reactions of N,N,N’,N’-tetramethylguanidine (TMG) with carbodiimides to synthesize hexasubstituted ...
Scheme 40: Microwave-assisted addition of N,N,N’,N’-tetramethylguanidine to carbodiimides [80].
Scheme 41: Synthesis of N1-aryl heptasubstituted biguanides via a one-pot biguanide formation–copper-catalyzed ...
Scheme 42: Formation of 1,2-dihydro-1,3,5-triazine derivatives by the reaction of guanidine with excess carbod...
Scheme 43: Plausible mechanism for the spontaneous cyclization of triguanides [82].
Scheme 44: a) Formation of mono- and disubstituted (iso)melamine derivatives by the reaction of biguanides and...
Scheme 45: Reactions of 2-aminopyrimidine with carbodiimides to synthesize 2-guanidinopyrimidines as “biguanid...
Scheme 46: Non-catalyzed alternatives for the addition of 2-aminopyrimidine derivatives to carbodiimides. A) h...
Scheme 47: Addition of guanidinomagnesium halides to substituted cyanamides [90].
Scheme 48: Microwave-assisted synthesis of [11C]metformin by the reaction of 11C-labelled dimethylcyanamide an...
Scheme 49: Formation of 4-amino-6-dimethylamino[1,3,5]triazin-2-ol through the reaction of Boc-guanidine and d...
Scheme 50: Formation of 1,3,5-triazine derivatives via the addition of guanidines to substituted cyanamides [92].
Scheme 51: Synthesis of biguanide by the reaction of O-alkylisourea and guanidine [93].
Scheme 52: Aromatic nucleophilic substitution of guanidine on 2-O-ethyl-1,3,5-triazine [95].
Scheme 53: Synthesis of N1,N2-disubstituted biguanides by the reaction of guanidine and thioureas in the prese...
Scheme 54: Cyclization reactions involving condensations of guanidine(-like) structures with thioureas [97,98].
Scheme 55: Condensations of guanidine-like structures with thioureas [99,100].
Scheme 56: Condensations of guanidines with S-methylisothioureas [101,102].
Scheme 57: Addition of 2-amino-1,3-diazaaromatics to S-alkylisothioureas [103,104].
Scheme 58: Addition of guanidines to 2-(methylsulfonyl)pyrimidines [105].
Scheme 59: An example of a cyclodesulfurization reaction to a fused 3,5-diamino-1,2,4-triazole [106].
Scheme 60: Ring-opening reactions of 1,3-diaryl-2,4-bis(arylimino)-1,3-diazetidines [107].
Scheme 61: Formation of 3,5-diamino-1,2,4-triazole derivatives via addition of hydrazines to 1,3-diazetidine-2...
Scheme 62: Formation of a biguanide via the addition of aniline to 1,2,4-thiadiazol-3,5-diamines, ring opening...
Figure 4: Substitution pattern of biguanides accessible by synthetic pathways a–h.
Mechanochemical synthesis of thioureas, ureas and guanidines
- Vjekoslav Štrukil
Beilstein J. Org. Chem. 2017, 13, 1828–1849, doi:10.3762/bjoc.13.178
- ) and glibenclamide (2), which belong to the class of sulfonylureas, and guanidine-derived metformin (3) are among the top selling oral hypoglycemics globally. Proguanil (4), a biguanide derivative, is widely prescribed to treat malaria, a disease that took over 430 000 lives in 2015 [6]. In the past 20
- –N bond of benzamide and the formation of N-acylsulfonylguanidine 48 extended by two atoms (Scheme 21b). Biguanides The attachment of an amidine subunit onto the guanidine core, which is typically accomplished by the addition of a carbodiimide molecule, leads to a biguanide framework. In a paper by
Graphical Abstract
Scheme 1: a) Schematic representations of unsubstituted urea, thiourea and guanidine. b) Wöhler's synthesis o...
Figure 1: Antidiabetic (1–3) and antimalarial (4) drugs derived from ureas and guanidines currently available...
Scheme 2: The structures of some representative (thio)urea and guanidine organocatalysts 5–8 and anion sensor...
Scheme 3: Solid-state reactivity of isothiocyanates reported by Kaupp [30].
Scheme 4: a) Mechanochemical synthesis of aromatic and aliphatic di- and trisubstituted thioureas by click-co...
Figure 2: The supramolecular level of organization of thioureas in the solid-state.
Figure 3: The supramolecular level of organization of thioureas in the solid-state.
Scheme 5: Thiourea-based organocatalysts and anion sensors obtained by click-mechanochemical synthesis.
Scheme 6: Mechanochemical desymmetrization of ortho-phenylenediamine.
Scheme 7: Mechanochemical desymmetrization of para-phenylenediamine.
Scheme 8: a) Selected examples of a mechanochemical synthesis of aromatic isothiocyanates from anilines. b) O...
Scheme 9: In solution, aromatic N-thiocarbamoyl benzotriazoles 27 are unstable and decompose to isothiocyanat...
Scheme 10: Mechanosynthesis of a) bis-thiocarbamoyl benzotriazole 29 and b) benzimidazole thione 31. c) Synthe...
Figure 4: In situ Raman spectroscopy monitoring the synthesis of thiourea 28d in the solid-state. N-Thiocarba...
Scheme 11: a) The proposed synthesis of monosubstituted thioureas 32. b) Conversion of N-thiocarbamoyl benzotr...
Scheme 12: A few examples of mechanochemical amination of thiocarbamoyl benzotriazoles by in situ generated am...
Scheme 13: Mechanochemical synthesis of a) anion binding urea 33 by amine-isocyanate coupling and b) dialkylur...
Scheme 14: a) Solvent-free milling synthesis of the bis-urea anion sensor 35. b) Non-selective desymmetrizatio...
Scheme 15: a) HOMO−1 contours of mono-thiourea 19b and mono-urea 36. b) Mechanochemical synthesis of hybrid ur...
Scheme 16: Synthesis of ureido derivatives 38 and 39 from KOCN and hydrochloride salts of a) L-phenylalanine m...
Scheme 17: a) K2CO3-assisted synthesis of sulfonyl (thio)ureas. b) CuCl-catalyzed solid-state synthesis of sul...
Scheme 18: Two-step mechanochemical synthesis of the antidiabetic drug glibenclamide (2).
Scheme 19: Derivatization of saccharin by mechanochemical CuCl-catalyzed addition of isocyanates.
Scheme 20: a) Unsuccessful coupling of p-toluenesulfonamide and DCC in solution and by neat/LAG ball milling. ...
Scheme 21: a) Expansion of the saccharin ring by mechanochemical insertion of carbodiimides. b) Insertion of D...
Scheme 22: Synthesis of highly basic biguanides by ball milling.
Come-back of phenanthridine and phenanthridinium derivatives in the 21st century
- Lidija-Marija Tumir,
- Marijana Radić Stojković and
- Ivo Piantanida
Beilstein J. Org. Chem. 2014, 10, 2930–2954, doi:10.3762/bjoc.10.312
- a design of derivatives equipped with biguanide groups at 3 and/or 8 positions [58] (Figure 3), under the presumption that the extended H-bond-rich system should increase the ability of the chromophore to differ among various shapes of ds-DNA- and ds-RNA-grooves. Both, mono- (3) and bis-biguanide (4
Graphical Abstract
Scheme 1: The Grignard-based synthesis of 6-alkyl phenanthridine.
Scheme 2: Radical-mediated synthesis of 6-arylphenanthridine [14].
Scheme 3: A t-BuO• radical-assisted homolytic aromatic substitution mechanism proposed for the conversion of ...
Scheme 4: Synthesis of 5,6-unsubstituted phenanthridine starting from 2-iodobenzyl chloride and aniline [17].
Scheme 5: Phenanthridine synthesis initiated by UV-light irradiation photolysis of acetophenone O-ethoxycarbo...
Scheme 6: PhI(OAc)2-mediated oxidative cyclization of 2-isocyanobiphenyls with CF3SiMe3 [19,20].
Scheme 7: Targeting 6-perfluoroalkylphenanthridines [21,22].
Scheme 8: Easily accessible biphenyl isocyanides reacting under mild conditions (room temp., visible light ir...
Scheme 9: Microwave irradiation of Diels–Alder adduct followed by UV irradiation of dihydrophenanthridines yi...
Scheme 10: A representative palladium catalytic cycle.
Scheme 11: The common Pd-catalyst for the biphenyl conjugation results simultaneously in picolinamide-directed...
Scheme 12: Pd(0)-mediated cyclisation of imidoyl-selenides forming 6-arylphenanthridine derivatives [16]. The inse...
Scheme 13: Palladium-catalysed phenanthridine synthesis.
Scheme 14: Aerobic domino Suzuki coupling combined with Michael addition reaction in the presence of a Pd(OAc)2...
Scheme 15: Rhodium-catalysed alkyne [2 + 2 + 2] cycloaddition reactions [36].
Scheme 16: The O-acetyloximes derived from 2′-arylacetophenones underwent N–O bond cleavage and intramolecular ...
Scheme 17: C–H arylation with aryl chloride in the presence of a simple diol complex with KOt-Bu (top) [39]; for s...
Scheme 18: The subsequent aza-Claisen rearrangement, ring-closing enyne metathesis and Diels–Alder reaction – ...
Scheme 19: Phenanthridine central-ring cyclisation with simultaneous radical-driven phosphorylation [42].
Scheme 20: Three component reaction yielding the benzo[a]phenanthridine core in excellent yields [44].
Scheme 21: a) Reaction of malononitrile and 1,3-indandione with BEP to form the cyclised DPP products; b) pH c...
Figure 1: Schematic presentation of the intercalative binding mode by the neighbour exclusion principle and i...
Figure 2: Urea and guanidine derivatives of EB with modified DNA interactions [57].
Figure 3: Structure of mono- (3) and bis-biguanide (4) derivative. Fluorescence (y-axis normalised to startin...
Scheme 22: Bis-phenanthridinium derivatives (5–7; inert aliphatic linkers, R = –(CH2)4– or –(CH2)6–): rigidity...
Figure 4: Series of amino acid–phenanthridine building blocks (general structure 10; R = H; Gly) and peptide-...
Figure 5: General structure of 45 bis-ethidium bromide analogues. Reproduced with permission from [69]. Copyright...
Scheme 23: Top: Recognition of poly(U) by 12 and ds-polyAH+ by 13; bottom: Recognition of poly(dA)–poly(dT) by ...
Figure 6: The bis-phenanthridinium–adenine derivative 15 (LEFT) showed selectivity towards complementary UMP;...
Figure 7: The neomycin–methidium conjugate targeting DNA:RNA hybrid structures [80].
Figure 8: Two-colour RNA intercalating probe for cell imaging applications: Left: Chemical structure of EB-fl...
Figure 9: The ethidium bromide nucleosides 17 (top) and 18 (bottom). DNA duplex set 1 and 2 (E = phenanthridi...
Figure 10: Left: various DNA duplexes; DNA1 and DNA2 used to study the impact on the adjacent basepair type on...
Figure 11: Structure of 4,9-DAP derivative 19; Rright: MIAPaCa-2 cells stained with 10 μM 19 after 60 and 120 ...
Figure 12: Examples of naturally occurring phenanthridine analogues.
