Amidine Function Research Articles

Catalyst-Free, Three-Component Synthesis of Amidinomaleimides.

Maleimide and amidine functionalities often appear in medicinal and natural product targets. We describe a catalyst-free, three-component coupling reaction for the synthesis of amidinomaleimides. This one-pot reaction fuses a broad range of secondary amines and aldehydes with azidomaleimides. The conditions are mild, simple, modular, high yielding, and amenable to aqueous solvents. Most reaction products can be sufficiently purified without column chromatography. The synthesis creates complex, multifunctional molecules with four different molecules, including a tripeptide, arrayed around an amidinomaleimide core.

Phenoxy-Amidine Ligands: Toward Lactic Acid-Tolerant Catalysts for Lactide Ring-Opening Polymerization

The replacement of the imine functionality in the ubiquitous phenoxy-imine (FI) ligands by a more robust and donor N,N,N′-trisubstituted amidine function was examined and gave rise to the synthesis of five new phenoxy-amidine (FA) ligands (L1–L5). The solid-state structure of four proligands has been determined by X-ray diffraction analysis and showed that the amidine moiety is in a trans-configuration. The reaction of the phenol-amidine proligands with AlMe3 afforded mononuclear (L1–L5)AlMe2 (1a–5a). A similar alkane elimination route was used from ZnEt2 and led to dinuclear [(L1–L5)ZnEt]2 complexes (1b–5b) or to homoleptic (L2/L4)2Zn complexes (2b′, 4b′) depending on the metal/ligand ratio used. The structure of these complexes has been determined by NMR spectroscopy (1H, 13C, HMBC, HSQC, DOSY, and NOESY experiments) and X-ray diffraction study for seven of them. The crystal structure of the Al complexes showed FA ligands coordinated in a chelate fashion via the O atom of the aryloxy group and the imino-N atom, indicating that the amidine function has undergone trans–cis isomerization upon coordination. A similar chelating coordination mode was observed for the FA ligands with Zn metal ions. These complexes were used as initiators for the ring-opening polymerization of rac-lactide. FA–Zn complexes gave the best performance, affording polylactic acid with a narrow molecular weight distribution and heterotactic bias (Pr up to 0.75). Remarkably, some of these complexes were able to tolerate the presence of a large amount of lactic acid to the point of using it as a co-initiator during the polymerization reaction.

Degradation of mirubactin to multiple siderophores with varying Fe(III) chelation properties.

Three siderophores mirubactins B-D (4-6) were identified as the degradation products of previously isolated mirubactin (1). Their structures were revealed by HR-ESI-MS/MS, NMR analyses, and density functional calculations, among which 4 contains an unusual cyclic amidine functionality. Cyclic voltammetry showed that 5 and 6 have reduced iron complexing capacity. Mirubactin (1) and Fe(III) could also form a stable complex, which may be an ingenious approach to compete for iron acquisition by the producing organisms.

A facile approach towards amidinophenylalanine derivatives as building blocks for the synthesis of non-natural peptides and peptidomimetics

The amidine function is extensively utilized as synthetic intermediate for structurally diverse heterocycles and as a core element in drugs and drug candidates. This study describes a facile and convenient approach for the highly efficient synthesis of amidinophenylalanine derivatives via the reduction of amidoximophenylalanines in the presence of Ac2O/AcOH/Zn at room temperature. The described process is attractive for process and medicinal chemistry due to its facility, safety, low cost, applicability for hydrogenation-sensitive compounds, and efficiency. Using this method, amidinophenylalanine derivatives as building blocks for peptides were obtained in excellent yields.

Reversal of polarity by catalytic SET oxidation: synthesis of azabicyclo[m.n.0]alkanes via chemoselective reduction of amidines.

A one-pot catalytic method has been developed for the stereoselective synthesis of cyclopropane-fused cyclic amidines using CuBr2/K2S2O8 as an efficient single electron transfer (SET) oxidative system. The generality of this mild method is demonstrated with a wide variety of substrates to furnish pharmaceutically important amidines containing aza-bicyclic and novel aza-tricyclic frameworks in very good yields. A chemoselective reduction of cyclic amidines to 2-/3-azabicyclo[m.n.0]alkanes and octahydroindoles has been developed using a NaBH4/I2 reagent system. The synthetic scope of the chemoselective reduction of the amidine functionality has been exemplified in the stereoselective synthesis of an iminosugar based (±)-epiquinamide analogue.

Proton-controlled non-exponential photoluminescence in a pyridylamidine-substituted Re(I) complex.

Chemical intuition and well-known design principles can typically be used to create ligand environments in transition metal complexes to deliberately tune reactivity for desired applications. However, intelligent ligand design does not always result in the expected outcomes. Herein we report the synthesis and characterization of a tricarbonyl rhenium (2,2'-bipyridine) 4-pyridylamidine, Re(4-Pam), complex with unexpected photophysical properties. Photoluminescence kinetics of Re(4-Pam) undergoes non-exponential decay, which can be deconvolved into two emission lifetimes. However, upon protonation of the amidine functionality of the 4-pyridylamidine to form Re(4-PamH), a single exponential decay is observed. To understand and rationalize these experimental observations, density functional theory (DFT) and time-dependent density functional theory (TDDFT) are employed. The symmetry or asymmetry of the protonated or deprotonated 4-pyridylamidine ligand, respectively, is the key factor in switching between one and two photoluminescence lifetimes. Specifically, rotation of the dihedral angle formed between the bipyridine and 4-Pam ligand leads to two rotamers of Re(4-Pam) with degenerate triplet- to ground-state transitions.

Amidine Functionality As a Conformational Probe of Cyclic Peptides.

The amidine functionality switches between hydrogen bond donor and acceptor roles depending on pH. Herein, the amidine was incorporated to select amides in cyclo(d-Ala-Pro-d-Phe-Pro-Gly). The unprotonated amidine-containing macrocyclic conformation resembles its oxoamide counterpart. Upon protonation, minimal alterations in the macrocyclic conformation were observed despite changes to the hydrogen bond network. The amidine disrupts hydrogen bonding at minimal steric cost, making it a useful functionality to study the effect of hydrogen bonding on the macrocyclic conformation.

Evaluation of a Series of β-Secretase 1 Inhibitors Containing Novel Heteroaryl-Fused-Piperazine Amidine Warheads.

Despite several years of research, only a handful of β-secretase (BACE) 1 inhibitors have entered clinical trials as potential therapeutics against Alzheimer's disease. The intrinsic basic nature of low molecular weight, amidine-containing BACE 1 inhibitors makes them far from optimal as central nervous system drugs. Herein we present a set of novel heteroaryl-fused piperazine amidine inhibitors designed to lower the basicity of the key, enzyme binding, amidine functionality. This study resulted in the identification of highly potent (IC50 ≤ 10 nM), permeable lead compounds with a reduced propensity to suffer from P-glycoprotein-mediated efflux.

Stereodiversified Modular Synthesis of Non‐planar Five‐Membered Cyclic N‐Hydroxylamidines: Reactivity Study and Application to the Synthesis of Cyclic Amidines

AbstractA modular, stereodiversified and scalable synthesis of 5‐membered cyclic N‐hydroxylamidines endowed with three contiguous stereogenic centres is reported. The synthesis utilizes 2‐cyano‐3‐aryl‐4‐nitro‐alkynoates as key building blocks, which are provided by a novel 3‐component Knoevenagel ‐Michael addition manifold carried out as an aqueous emulsion (on water). The key building blocks are obtained as separable mixtures of two series of diastereomers: 2,3,4‐syn,syn and 2,3,4‐syn,anti. Both series were separately transformed into the corresponding 5‐membered 3,4,5‐trisubstituted N‐hydroxylamidines by a tandem hydrogenation cyclization reaction (stereodiversification phase). These N‐hydroxylamidines are functionalized at C3‐methinic position of the ring (alpha to the amidine function) by a robust and unprecedented N‐amidinoxyl radical‐mediated auto‐oxidation process (hydroxylation), or by a diastereoselective enamine‐based C−C bond forming manifold (creation of an all‐carbon quaternary centre). The outcome of the latter is biased by the relative disposition of substituents in the ring, affording C3‐quaternized 5‐membered cyclic N‐hydroxylamidines or 2,9‐diazabicyclo[4.3.0]non‐1‐en motives. Finally, the Ti(III)‐reduction of these quaternized N‐hydroxylamidines generates the corresponding amidines in excellent yields.magnified image

Unusual phenethylamine-containing alkaloids from Elaeocarpus tectorius

From the leaves of Elaeocarpus tectorius (Lour.) Poir. four previously undescribed phenethylamine-containing alkaloids were isolated, namely, tectoricine, possessing an unprecedented isoquinuclidinone ring system incorporating a phenethylamine moiety, tectoraline, representing a rare alkamide incorporating two phenethylamine moieties, and tectoramidines A and B, representing the first naturally occurring trimeric and dimeric phenethylamine alkaloids incorporating an amidine function. The structures of these alkaloids were established by detailed spectroscopic analysis. The absolute configuration of tectoricine was determined by comparison of the experimental and calculated ECD spectra. Plausible biosynthetic pathways to the four alkaloids are proposed.

Amidinoquinoxaline N-oxides: spin trapping of O- and C-centered radicals.

Amidinoquinoxaline N-oxides represent a novel family of heterocyclic spin traps. In this work, their ability to trap O- and C-centered radicals was tested using selected derivatives with different structural modifications. All the studied nitrones were able to trap radicals forming persistent spin adducts, also in the case of OH and OOH radicals which are of wide biological interest as examples of ROS. The stability of the adducts was mainly attributed to the wide delocalization of the unpaired electron over the whole quinoxaline moiety. The nitroxide spectral parameters (hfccs and g-factors) were analyzed and the results were supported by DFT calculations. The N-19 hfccs and g-factors were characteristic of each aminoxyl and could aid in the identification of the trapped radical. The enhanced stability of the OH adducts under the employed reaction conditions could be ascribed to their possible stabilization by IHBs with two different acceptors: the N-O˙ moiety or the amidine functionality. DFT calculations indicate that the preferred IHB is strongly conditioned by the amidine ring size. While five membered homologues show a clear preference for the IHB with the N-O˙ group, in six membered derivatives this stabilizing interaction is preferentially established with the amidine nitrogen as an IHB acceptor.

Surprisingly Different Reaction Behavior of Alkali and Alkaline Earth Metal Bis(trimethylsilyl)amides toward Bulky N-(2-Pyridylethyl)-N'-(2,6-diisopropylphenyl)pivalamidine.

N-(2,6-Diisopropylphenyl)-N'-(2-pyridylethyl)pivalamidine (Dipp-N=C(tBu)-N(H)-C2 H4 -Py) (1), reacts with metalation reagents of lithium, magnesium, calcium, and strontium to give the corresponding pivalamidinates [(tmeda)Li{Dipp-N=C(tBu)-N-C2 H4 -Py}] (6), [Mg{Dipp-N=C(tBu)-N-C2 H4 -Py}2 ] (3), and heteroleptic [{(Me3 Si)2 N}Ae{Dipp-N=C(tBu)-N-C2 H4 -Py}], with Ae being Ca (2 a) and Sr (2 b). In contrast to this straightforward deprotonation of the amidine units, the reaction of 1 with the bis(trimethylsilyl)amides of sodium or potassium unexpectedly leads to a β-metalation and an immediate deamidation reaction yielding [(thf)2 Na{Dipp-N=C(tBu)-N(H)}] (4 a) or [(thf)2 K{Dipp-N=C(tBu)-N(H)}] (4 b), respectively, as well as 2-vinylpyridine in both cases. The lithium derivative shows a similar reaction behavior to the alkaline earth metal congeners, underlining the diagonal relationship in the periodic table. Protonation of 4 a or the metathesis reaction of 4 b with CaI2 in tetrahydrofuran yields N-(2,6-diisopropylphenyl)pivalamidine (Dipp-N=C(tBu)-NH2 ) (5), or [(thf)4 Ca{Dipp-N=C(tBu)-N(H)}2 ] (7), respectively. The reaction of AN(SiMe3 )2 (A=Na, K) with less bulky formamidine Dipp-N=C(H)-N(H)-C2 H4 -Py (8) leads to deprotonation of the amidine functionality, and [(thf)Na{Dipp-N=C(H)-N-C2 H4 -Py}]2 (9 a) or [(thf)K{Dipp-N=C(H)-N-C2 H4 -Py}]2 (9 b), respectively, are isolated as dinuclear complexes. From these experiments it is obvious, that β-metalation/deamidation of N-(2-pyridylethyl)amidines requires bases with soft metal ions and also steric pressure. The isomeric forms of all compounds are verified by single-crystal X-ray structure analysis and are maintained in solution.

Synthesis and anti-tubercular activity of N(2)-arylbenzo[g]isoquinoline-5,10-dione-3-iminium bromides.

Tuberculosis has remained a challenge for medicinal chemists worldwide. In the framework of a collaborative program to identify and evaluate novel antitubercular candidate compounds, the biological properties of benzo[g]isoquinoline-5,10-diones have been found to be very promising. In this paper we have further expanded the library by incorporation of an amidinium moiety into the benzo[g]isoquinoline-5,10-dione scaffold. The presence of this functional group also increased the solubility of the quinones in polar solvents. To this purpose N(2)-arylbenzo[g]isoquinoline-5,10-dione-3-iminium bromides were synthesized in a straightforward way by means of a reaction of anilines with 2-(bromomethyl)-3-(cyanomethyl)-1,4-dimethoxynaphthalene. Following the biological evaluation, N(2)-(4-chlorophenyl)-5,10-dioxobenzo[g]isoquinoline-3(2H)-iminium bromide (MIC = 1.16 μM, CC50 = 28.51 μM, SI = 24.58) was selected as the most promising representative. Apart from the nano-molar anti-mycobacterial activity, the compound was able to target intracellular residing Mycobacterium tuberculosis and the susceptibility of a multi-drug-resistant strain towards the compound was confirmed.

Experimental and theoretical studies on the tautomerism and reactivity of isoxazolo[3,4-b]quinolin-3(1H)-ones

A variety of substituted isoxazolo[3,4-b]quinolin-3(1H)-ones incorporating an ambident amidine functionality was synthesized by a two-step procedure starting from the corresponding 2-chloroquinoline-3-carboxylic acids. Alkylation and acylation reactions carried out in DMF solution in the presence of Et3N occurred preferentially on the available σ lone pair of the pyridine-type N1 nitrogen atom of the most stable 9H-oxo tautomer. The use of sodium hydroxide in place of Et3N led to isoxazolone ring cleavage with the formation of alkyl 2-(alkoxy(alkyl)amino)quinoline-3-carboxylates. The electronic structure of the three possible N1-oxo, N9-oxo and 3-hydroxy tautomeric forms, and the NaOH-induced cleavage of the isoxazolone ring were studied theoretically with use of the B3LYP/6-31+G* density functional method and SM8 (DMF) solvation model. The synthesized N1-alkyl and N1-acyl derivatives of isoxazolo[3,4-b]quinolin-3(1H)-one were evaluated for their in vitro antifungal activity against 19 pathogenic yeast-like fungal strains.

Isolation and identification of novel natural products that inhibit P300/HIF-1α interaction

Hypoxia-inducible factor-1 (HIF-1) is an important transcription factor for initiating a response against low oxygen environments in many solid tumors. Under hypoxic conditions, subunit HIF-1α dimerizes with subunit HIF-1β and binds to the multi-domain protein and transcriptional coactivator, p300. Inhibition of the p300/HIF-1α interaction results in the suppression of HIF-1 transcriptional activity during hypoxia. An extract of the marine ascidian Eudistoma sp. was identified as active in a high throughput screen for inhibitors of the p300/HIF-1α interaction. Three novel heterocylic alkaloids were isolated from the extract and their structures elucidated using both spectroscopic analyses and synthesis. The core scaffold of these alkaloids contains an unprecedented fused ring system with embedded guanidine and amidine functionalities. These compounds showed activity inhibiting the binding domains of p300 and HIF-1α.

Isolation and identification of novel natural products that inhibit P300/HIF-1α interaction

Hypoxia-inducible factor-1 (HIF-1) is an important transcription factor for initiating a response against low oxygen environments in many solid tumors. Under hypoxic conditions, subunit HIF-1α dimerizes with subunit HIF-1β and binds to the multi-domain protein and transcriptional coactivator, p300. Inhibition of the p300/HIF-1α interaction results in the suppression of HIF-1 transcriptional activity during hypoxia. An extract of the marine ascidian Eudistoma sp. was identified as active in a high throughput screen for inhibitors of the p300/HIF-1α interaction. Three novel heterocylic alkaloids were isolated from the extract and their structures elucidated using both spectroscopic analyses and synthesis. The core scaffold of these alkaloids contains an unprecedented fused ring system with embedded guanidine and amidine functionalities. These compounds showed activity inhibiting the binding domains of p300 and HIF-1α.

Lewis Acid‐Catalyzed or Base‐Promoted Regioselective Cycloisomerization of N‐Imidoyl‐o‐alkynylanilines for Synthesis of N‐Imidoyl‐(1 H)‐indoles and 4‐Alkylidene‐3,4‐dihydroquinazolines

AbstractProduct selectivity control for the synthesis of imidoylindoles and 4‐alkylidenedihydroquinazolines from N‐imidoyl‐o‐alkynylanilines via silver triflate‐catalyzed cycloisomerization or tetrabutylammonium fluoride‐promoted cyclization is described. The product selectivity depends mainly on the catalyst/promoter used, and on the substituents on the alkyne and amidine functions of the substrates.magnified image

ChemInform Abstract: Synthesis of Functionalized Pyridine‐2,6‐bis(imidazolines) by Ring Transformation of 4‐(Aminomethyl)oxazoline Derivatives.

Optically active pyridine-2,6-bis(4-azidomethyloxazoline) was prepared by starting from L-serine and pyridine 2,6-dicarboxylic acid. Reduction of the azide moieties gave pyridine-2,6-bis(4-aminomethyloxazoline), which was not a stable compound, but readily underwent a ring-transforming rearrangement to furnish the pyridine-2,6-bis(4-hydroxymethylimidazoline). After Boc protection of the amidine functionalities, this compound could be further converted into the pyridine-2,6-bis(4-aminomethylimidazoline) via the corresponding bis(azidomethyl) compound. The azide functions of the bis(oxazoline) and the bis(imidazoline) intermediate products could also be further derivatized with an alkyne to give triazoles or through aza-Wittig reactions with benzaldehyde to give imines.

ChemInform Abstract: The Synthesis of Vinylogous Amidine Heterocycles.

We report herein a convenient synthetic methodology for the conversion of meta-dinitro heterocyclic rings to iminoquinones with vinylogous amidine functionality. These structures are found in nature, particularly in marine organisms, and may be important for the pigments and biological activity observed with such marine secondary metabolites. Using benzimidazole and indole ring systems we show the versatility of these vinylogous amidines for organic synthesis, including the following: transamination substitution reactions with virtually any primary amine, regional control of the substitution with substituents between the vinylogous amidine, and hydrolytic properties that can be controlled or optimized based on the properties of the chosen ring system. Taken together, this versatile chemistry and functionalization of organic molecules may be useful in the preparation of a variety of chemical products such as drug pharmacophores or assembling macromolecular structures.

The Synthesis of Vinylogous Amidine Heterocycles

We report herein a convenient synthetic methodology for the conversion of meta-dinitro heterocyclic rings to iminoquinones with vinylogous amidine functionality. These structures are found in nature, particularly in marine organisms, and may be important for the pigments and biological activity observed with such marine secondary metabolites. Using benzimidazole and indole ring systems we show the versatility of these vinylogous amidines for organic synthesis, including the following: transamination substitution reactions with virtually any primary amine, regional control of the substitution with substituents between the vinylogous amidine, and hydrolytic properties that can be controlled or optimized based on the properties of the chosen ring system. Taken together, this versatile chemistry and functionalization of organic molecules may be useful in the preparation of a variety of chemical products such as drug pharmacophores or assembling macromolecular structures.