Guanidine Unit Research Articles

Organocatalytic Stereoselective [8+2] Cycloaddition of Tropones with Azlactones

Organocatalytic Stereoselective [8+2] Cycloaddition of Tropones with Azlactones

Artificial Host Molecules to Covalently Capture 8-Nitro-cGMP in Neutral Aqueous Solutions and in Cells.

New 1,3-diazaphenoxazine derivatives (nitroG-Grasp-Guanidine, NGG) have been developed to covalently capture 8-nitro-cGMP in neutral aqueous solutions, which furnish a thiol reactive group to displace the 8-nitro group and a guanidine unit for interaction with the cyclic phosphate. The thiol group was introduced to the 1,3-diazaphenoxazine skeleton through a 2-aminobenzylthiol group (NGG-H) and its 4-methyl (NGG-pMe) and 6-methyl (NGG-oMe) substituted derivatives. The covalent adducts were formed between the NGG derivatives and 8-nitro-cGMP in neutral aqueous solutions. Among the NGG derivatives, the one with the 6-methyl group (NGG-oMe) exhibited the most efficient capture reaction. Furthermore, NGG-H showed a cell permeability into HEK-293 and RAW 264.7 cells and reduced the intracellular 8-nitro-cGMP level. The NGG derivatives developed in this study would become a valuable tool to study the intracellular role of 8-nitro-cGMP.

The protonation state governs the coordination of phosphinoferrocene guanidines

Protonation state of the guanidine unit in phosphinoferrocene guanidines controls the coordination behaviour of these hybrid P,N-ligands.

Synthesis of Saxitoxin and Its Derivatives.

The chiral synthesis of (+)-saxitoxin and its derivatives is described. Two consecutive carbon-nitrogen bonds at C-5 and C-6 in saxitoxin were effectively installed by the sequential Overman rearrangement of an allylic vicinal diol derived from d-malic acid. The bicyclic guanidine unit was constructed by the intramolecular aminal formation of an acyclic bis-guanidine derivative possessing a ketone carbonyl at C-4. From the bicyclic aminal intermediate, (+)-saxitoxin, (+)-decarbamoyl-β-saxitoxinol [(+)-dc-β-saxitoxinol], and the unnatural skeletal isomer, (-)-iso-dc-saxitoxinol, were synthesized.

Total Synthesis of (+)-Guadinomic Acid via Hydroxyl-Directed Guanidylation.

Protecting-group-free total synthesis of (+)-guadinomic acid is reported using δ-valerolactone as a readily available starting material. The protocol utilizes the recent hydroxyl-directed guanidylation of unactivated alkenes as an approach for direct stereoselective incorporation of the guanidine unit furnishing the natural product in 7 steps.

Stereoselective Synthesis of Cyclic Guanidines by Directed Diamination of Unactivated Alkenes.

A method for a directed stereoselective guanidinylation of alkenes is described. The guanidine unit can be delivered as an intact fragment by a hydroxy or carboxy group, usually with a high level of stereocontrol. After the guanidine delivery, the directing group can be cleaved under exceptionally mild conditions, typically by alcoholysis in the presence of acetic acid. Broad functional group tolerance and mild reaction conditions for the cycloguanidilation suggest applications in medicinal chemistry and natural products synthesis.

Synthesis, structure, and properties of SrC(NH)3 , a nitrogen-based carbonate analogue with the trinacria motif.

Strontium guanidinate, SrC(NH)3 , the first compound with a doubly deprotonated guanidine unit, was synthesized from strontium and guanidine in liquid ammonia and characterized by X-ray and neutron diffraction, IR spectroscopy, and density-functional theory including harmonic phonon calculations. The compound crystallizes in the hexagonal space group P63 /m, constitutes the nitrogen analogue of strontium carbonate, SrCO3 , and its structure follows a layered motif between Sr(2+) ions and complex anions of the type C(NH)3 (2-) ; the anions adopt the peculiar trinacria shape. A comparison of theoretical phonons with experimental IR bands as well as quantum-chemical bonding analyses yield a first insight into bonding and packing of the formerly unknown anion in the crystal.

N,N,N'-Trimethyl-N''-(4-nitro-phen-yl)-N'-phenyl-guanidine.

The C—N bond lengths in the guanidine unit of the title compound, C16H18N4O2, are 1.298 (2), 1.353 (2) and 1.401 (3) Å, indicating double- and single-bond character. The N—C—N angles are 115.81 (16), 118.90 (18) and 125.16 (18)°, showing a deviation of the CN3 plane from an ideal trigonal–planar geometry. In the crystal, C—H⋯O hydrogen bonds are observed between the methyl- and aromatic-H atoms and nitro-O atoms. One H atom of the phenyl ring and of the NMe2 group associate with the O atoms of the nitro group, giving chains along the a- and b-axis directions. Cross-linking of these two chains results in a two-dimensional network along bc.

Oseltamivir Analogues Bearing N-Substituted Guanidines as Potent Neuraminidase Inhibitors

A series of oseltamivir analogues bearing an N-substituted guanidine unit were prepared and evaluated as inhibitors of neuraminidases from four strains of influenza. The two most potent analogues identified contain relatively small N-guanidine substituents (N-methyl and N-hydroxyl) and display enhanced inhibition with IC50 values in the low nanomolar range against neuraminidases from wild-type and oseltamivir-resistant strains. Potential advantages of including the N-hydroxyguanidine moiety in neuraminidase inhibitors are also discussed.

N''-(4-Meth-oxy-phen-yl)-N,N,N'-trimethyl-N'-phenyl-guanidine.

In the title compound, C17H21N3O, the C—N bond lengths in the guanidine unit are 1.2889 (19), 1.3682 (19) and 1.408 (2) Å, indicating double- and single-bond character. The N—C—N angles are 115.10 (13), 119.29 (15) and 125.61 (14)°, showing a deviation of the CN3 plane from an ideal trigonal–planar geometry. In the crystal, non-classical C—H⋯O hydrogen bonds between methyl H atoms and meth­oxy O atoms are present, generating centrosymmetric dimers running in the [101] direction.

Insertion Reactions of Six-Membered Cyclopalladated N,N′,N″-Triarylguanidine, [Pd{κ2(C,N)-C6H3Me-3(NHC(NHAr)(═NAr))-2}(μ-Br)]2 (Ar = 2-MeC6H4) with PhC≡C—C(O)OR (R = Me and Et): A Gateway to Second Orthopalladation through Novel Rearrangements

The reaction of Pd{kappa(2)(C,N)-C6H3Me-3-(NHC(NHAr)(=NAr))-2}(mu-Br)](2) (Ar = 2-MeC6H4; 1) with 4 equiv of PhC C-C(O)OMe in CH2Cl2 afforded Pd{kappa(2)(C,N)-C(Ph)=C(C(O)OMe)C(Ph)=C(C(O)-OMe)C6H3Me-3(N=C(NH Ar)(2))-2}Br] (Ar = 2-MeC6H4; 2) in 70% yield, and the aforementioned reaction carried out with 10 equiv of PhC C-C(O)OR (R = Me, and Et) afforded an admixture of two regioisomers of Pd{kappa(3)(N,C,O)-O=C(OR)-C5Ph3(C(O)OR)C(C(O)OR)C6H3Me-3(N=C(NHAr)( 2))- 2}Br] (Ar = 2-MeC6H4; R = Me (3a/3b), Et (4a/4b)) in 80 and 87% yields, respectively. In one attempt, the minor regioisomer, 4b, was isolated from the mixture in 6% yield by fractional crystallization. Palladacycles 3a/3b and 4a/4b, upon stirring in CH2Cl2/MeCN (1/1, v/v) mixture at ambient condition for S days, afforded Pd{eta(3)-allyl,(KN)-N-1)-C-5(C(O)OR)(2)Ph3C-(C(O)OR)C6H3Me-3(N=C(NH Ar)(2))(-2)}Br] (Ar = 2-MeC6H4; R = Me (5a/5b), Et (6a/6b)) in 94 and 93% yields, respectively. Palladacycles 3a/3b and 4a/4b, upon reaction with AgOTf in CH2CH2/Me2C(O) (1/1, v/v) mixture at ambient temperature for 15 min, afforded Pd{kappa(3)(N,C,O)-O=C(OR)C5Ph3(C(O)OR)C(C(O)OR)C6H3Me-3(N=C(NHAr)(2 ))-2}(OTf)] (Ar = 2-MeC6H4; R = Me (7a/7b), Et (8a/8b)) in 79 and 77% yields, respectively. Palladacycles 7a/7b and 8a/ 8b, upon reflux in PhC1 separately for 6 h, or palladacycles 5a/5b and 6a/6b, upon treatment with AgOTf in CH2Cl2/Me2C(O) (7/3, v/v) mixture for 15 min, afforded Pd{(eta(2)-Ph)C5Ph2(C(O)OR)kappa(2)(C,N)-C(C(O)OR)C6H3Me-3(N=C(NHAr) (2))-2}(OTf)] (Ar = 2-MeC6H4; R = Me (9a/9h), Et (10a/10b)) in >= 87% yields. Palladacycles 9a/9b, upon stirring in MeCN in the presence of excess NaOAc followed by crystallization of the reaction mixture in the same solvent, afforded Pd{kappa(3)(N,C,C)-(C6H4)C5Ph2(C(O)OMe)(2)C(C(O)OMe)(2)C6H3Me-3(N=C( NHAr)(2))-2}(NCMe)] (Ar = 2-MeC6H4; 11a/11b) in 82% yield. The new palladacycles were characterized by analytical, IR, and NMR (H-1 and C-13) spectroscopic techniques, and the molecular structures of 2, 3a, 4a, 4b, 5a, 6a, 7a, 9a, 10a, and 11a-d(3) were determined by single crystal X-ray diffraction. The frameworks in the aforementioned palladacycles, except that present in 2, are unprecedented. Plausible pathways for the formation of new palladacycles and the influence of the guanidine unit in 1, substituents in alkynes, reaction conditions, and electrophilicity of the bromide and the triflate upon the frameworks of the insertion products have been discussed.

Divalent N(I) Character in 2-(Thiazol-2-yl)guanidine: An Electronic Structure Analysis

Several medicinally important compounds carry a 2-(thiazol-2-yl)guanidine unit. These species are generally (erroneously) represented as 1-(thiazol-2-yl)guanidine species. Quantum chemical studies were performed to identify the appropriate tautomeric state of this class of compounds. B3LYP/6-31+G(d) calculations indicate the preferred tautomeric state of these species is associated with the 2-(thiazol-2-yl)guanidine structure rather than the 1-(thiazol-2-yl)guanidine structure. G2MP2 calculations on the model system were carried out to study the electronic structure, electron delocalization, and protonation energy; MESP, ELF, HOMA, AIM, and NBO analyses were also carried out. The results indicate that this class of compounds may be treated as species with hidden ::N(←L)R character. Upon protonation of the thiazole ring nitrogen, these systems show the electronic structure as in ::N(←L)2(⊕) systems with divalent N(I) oxidation state.

Microwave‐Assisted Synthesis of Guanidine Organocatalysts Bearing a Tetrahydroisoquinoline Framework and Their Evaluation in Michael Addition Reactions

AbstractThe simple and practical syntheses of chiral guanidine organocatalysts and their evaluation in the asymmetric Michael addition reaction of malonates and β‐keto esters with nitro‐olefins is reported. These organocatalysts are the first of their kind based on a tetrahydroisoquinoline framework. In addition, a microwave‐assisted procedure for introducing the guanidine unit onto amino amide derivatives is reported. The chiral products were obtained with quantitative chemical efficiency (up to 99 % yield) and excellent enantioselectivity (up to 97 % ee).

2-(1,3-Benzothiazol-2-yl)guanidin-2-ium acetate

In the title compound, C8H9N4S−·C2H3O2 −, the cation is essentially planar (r.m.s deviation = 0.037 Å) with the guanidine unit bent out of the plane of the fused-ring system by 4.6 (3)°. In the asymmetric unit, the cations and anions are linked into R 2 2(8) motifs. In the crystal, further N—H⋯O and N—H⋯N hydrogen bonds link the components into a two-dimensional network.

Zinc Complexes with Guanidine–Pyridine Hybrid Ligands – Guanidine Effect and Catalytic Activity

AbstractTwo new series of guanidine–pyridine ligands have been synthesised by the reaction of various chloroformamidinium chlorides with 8‐aminoquinoline or 2‐picolylamine. The ligands were treated with either zinc chloride or zinc acetate to prepare the corresponding complexes, which were tested as initiators in the solvent‐free ring‐opening polymerisation of d,l‐lactide. The effect of the guanidine ligand on the catalytic activity of the zinc complexes was investigated. A great number of the synthesised complexes showed appreciable polymerisation activity. 13 new zinc guanidine complexes have been structurally characterised, including the first examples of structures comprising a tetraethylguanidine unit. The experimental results were complemented by a density functional study, which has probed the influence of substituents at the guanidine unit. Especially for the tetraethylguanidine systems, insights into the strength of delocalisation within guanidine moieties are provided.

CXCR3 antagonists: Quaternary ammonium salts equipped with biphenyl- and polycycloaliphatic-anchors

Small-molecule ligands for the CXCR3 chemokine receptor receive considerable attention as a means to interrogate the roles of CXCR3 in vitro and in vivo and/or to potentially treat various conditions such as inflammatory diseases and cancer. We have synthesized and explored a novel class of small-molecule antagonists for CXCR3. A medium-throughput screen revealed an adamantane-guanidine as a hit. The guanidine unit was replaced by a small quaternary ammonium group, leading to ca. 5-fold increase in affinity. Substitution of the adamantane group by a myrtenyl moiety further increased affinity, while the benzyl group was decorated with an additional (substituted) aryl ring. This led to the identification of several bisaryl-based ligands with CXCR3 affinities of around 100 nM and with the ability to antagonize the functional activity of CXCL10.

2-(1,3-Benzothiazol-2-yl)guanidine

In the title comound, C8H8N4S, one of the two independent mol­ecules is essentially planar (r.m.s. deviation = 0.025 Å), while the other is slightly buckled (r.m.s. deviation = 0.131 Å) with the guanidine unit bent out of the plane of the fused-ring system by 16.8 (1)°. In the crystal, inter­molecular N—H⋯N hydrogen bonds between the two independent mol­ecules give rise to a hydrogen-bonded dimer. Addtional weak inter­molecular N—H⋯N hydrogen bonds connect these dimers into chains along [010]. An intra­molecular N—H⋯N hydrogen bond is also observed in each independent mol­ecule.

Unprecedented 1,3-Diaza[3]ferrocenophane Scaffold as Molecular Probe for Anions

The guanidine unit in the guise of 2-aminoimidazole in the new structural motif 2-arylamino-1,3-diaza[3]ferrocenophane 4 acts as a binding site for anions. The electrochemical behavior of this compound has been studied by cyclic voltammetry (CV) and differential pulse voltammetry (DPV) and was found to exhibit a quasi reversible oxidation peak, associated to the Fe(II)/Fe(III) redox couple (Ep = 440 mV), and a non-reversible oxidation wave (Ep = 817 mV), probably associated to the oxidation of the C═N unit present in the guanidine bridge. Recognition of AcO(-), PhCO(2)(-), F(-), Cl(-), and Br(-) anions by the free receptor and the less basic anions Br(-), Cl(-), and NO(3)(-) by its monoprotonated form takes place by unusual redox-ratiometric measurements and spectroscopic ((1)H NMR and UV-vis) changes.

(Guanidine)copper complexes: structural variety and application in bioinorganic chemistry and catalysis

In this paper, guanidine copper compounds are reviewed with an emphasis on structural characteristics and their application in bioinorganic chemistry and catalysis. The literature survey includes the copper coordination chemistry of biological guanidine derivatives, peralkylated guanidines including bicyclic ones and of further nitrogen-rich guanidine-type systems such as azoimidazoles, triazolopyrimidines and triaminoguanidines. From a sporadic interest dating back to the 1960s, research on this ligand class and its use in copper coordination chemistry has gained new impetus since 2000. With the synthesis of examples with sophisticated substitution at the characteristic CN 3 framework, complex problems can be addressed in several fields of chemistry. This paper analyses the different types of guanidines for their special donor properties and highlights the specific advantages of guanidines as neutral donor ligands in copper coordination chemistry where a great variety of coordination modes was found. These compounds offer the ability to distribute the formal positive charge of the metal throughout the guanidine unit and represent more than simple σ-donating ligands.

Mechanistic studies on the ring-opening polymerisation of D,L-lactide with zinc guanidine complexes

The increasing shortage of resources has enforced the search for production techniques for biodegradable polymers made of renewable raw materials. An example is polylactide (PLA), an aliphatic polyester, which can be obtained by the metal-catalysed ring-opening polymerisation (ROP) of lactide (Fig. ​(Fig.1).1). The monomer for PLA production is available from corn or sugar beets by a bacterial fermentation process in few steps [1] The PLA can be either recycled or composted after use, making the use CO2-emission-neutral. Most large-scale processes are based on the use of tin compounds as initiators [2]. However, for use in food packaging or similar applications, heavy metals are undesirable [3]. Figure 1 ROP of D,L-lactide In order to substitute heavy-metal-based catalyst systems, especially zinc guanidine complexes are suited for the polymerisation due to their polymerisation activity and non-toxicity [4]. The investigations on the catalytic potential in the bulk polymerisation of lactide have shown that these compounds are able to act as initiators for lactide polymerisation with only few exceptions. Polylactides with molecular weights (MW) between 20.000 and 170.000 g/mol could be obtained. As the polymerisation activity depends strongly on the ligand structure (spacer, guanidine and amine unit), DFT studies on the complex properties have been performed [5]. A correlation between calculated partial charges on the zinc and the guanidine N atoms and the catalytic activity has been found. The guanidine is supposed to open nucleophilically the lactide ring and supersede the presence of alkoxides which is traditionally required. This crucial step in the ROP has been analysed by DFT and a mecha-nism will be presented. The deeper understanding of the catalytic transition state will enable a more efficient access to catalyst design. Figure ​Figure22. Figure 2 General motif for hybridquanidines