Benzylic Nitrogen Research Articles

Synthesis andin vivoEvaluation of Fluorobenzyl Metformin Derivatives as Potential Drugs in The Diabetes Treatment

AbstractMetformin is a versatile, biocompatible, and cheap bis‐guanidine used as first response line in the type II diabetes treatment. Since its first human trials (1956) several structural modifications were carried out to increase its activity. However, with this augmented activity, the biological compatibility diminishes, generating serious side effects, such as lactic acidosis. Considering that cytochrome P450 oversees the metformin metabolism and its weakness to eliminate fluorinated metabolites; we envisioned the synthesis of benzyl fluorinated metformin derivatives. In our hypothesis the fluorine atoms can give, by inductive effect, a higher acidity to the hydrogen in the benzylic nitrogen, increasing its solubility. On the other hand, fluorine would give resistance to cP450 allowing the molecule acting longer. Thus, a family of fourteen fluorobenzyl metformins were synthesized and characterized, then anin vitroenzymatic assay with α‐amylase was performed to select the five best performing compounds, then anin vivoexperiment was carried out with streptozotocin‐induced CD1 mice using the selected derivatives. Blood glucose was measured every day. After sacrifice, the lipid profile, serum, and liver γ‐glutamyl transferase (GGT) activity determined the biocompatibility. Results showed two compounds (1 Land1 M) with enhanced activity and higher biocompatibility for blood glucose, lipids metabolism and GGT activity regulation.

Reaction aminates C–H bonds selectively

Many approved drugs contain benzylic nitrogens, which can influence bioactivity substantially. A new catalytic reaction that adds amine groups to benzylic C–H bonds more selectively than was previously possible could be useful to derivatize molecules for drug discovery. M. Christina White of the University of Illinois, Urbana-Champaign, and coworkers employed manganese(III) perchlorophthalocyanine to catalyze amination of one benzylic C–H bond selectively in substrates with other benzylic sites (Nat. Chem. 2018, DOI: 10.1038/s41557-018-0020-0). Removing a sulfur-containing protecting group from the initial products generates the free-amine final products. In substrates with multiple benzylic sites, amination occurs preferably at the least sterically encumbered and most electron-rich benzylic C–H bond. In the presence of a Brønsted or Lewis acid, the reaction also works on substrates already containing basic nitrogens. Existing C–H amination methods either do not work for such compounds or they aminate C–H bonds adjacent to the nitrogen. White and coworkers used the

Oxetane Substrates of Human Microsomal Epoxide Hydrolase.

Oxetanyl building blocks are increasingly used in drug discovery because of the improved drug-like properties they confer on drug candidates, yet little is currently known about their biotransformation. A series of oxetane-containing analogs was studied and we provide the first direct evidence of oxetane hydrolysis by human recombinant microsomal epoxide hydrolase (mEH). Incubations with human liver fractions and hepatocytes were performed with and without inhibitors of cytochrome P450 (P450), mEH and soluble epoxide hydrolase (sEH). Reaction dependence on NADPH was investigated in subcellular fractions. A full kinetic characterization of oxetane hydrolysis is presented, in both human liver microsomes and human recombinant mEH. In human liver fractions and hepatocytes, hydrolysis by mEH was the only oxetane ring-opening metabolic route, with no contribution from sEH or from cytochrome P450-catalyzed oxidation. Minimally altering the structural elements in the immediate vicinity of the oxetane can greatly modulate the efficiency of hydrolytic ring cleavage. In particular, higher pKa in the vicinity of the oxetane and an increased distance between the oxetane ring and the benzylic nitrogen improve reaction rate, which is further enhanced by the presence of methyl groups near or on the oxetane. This work defines oxetanes as the first nonepoxide class of substrates for human mEH, which was previously known to catalyze the hydrolytic ring opening of electrophilic and potentially toxic epoxide-containing drugs, drug metabolites, and exogenous organochemicals. These findings will be of value for the development of biologically active oxetanes and may be exploited for the biocatalytic generation of enantiomerically pure oxetanes and diols.

Two New Compounds in the Group of Zinc Phenoxides and Zinc Phenylamides

The synthesis and characterization of ethyl{2‐[(phenylamino)methyl]phenoxy}zinc (1) and ethyl{2‐[(propan‐2‐ylideneamino)methyl]phenylamido}zinc (2) are reported. The phenoxide 1 was prepared starting from 2‐(phenylaminomethyl)phenol and diethylzinc and the phenylamide 2 was obtained from 2,2‐dimethyl‐1,2,3,4‐tetrahydroquinazoline and diethylzinc. The compounds were characterized by NMR spectroscopy (1H, 13C{1H}), IR spectroscopy, elemental analysis, TGA measurements, and X‐ray structure analysis. In the solid state both compounds form dimers where (1)2·4thf shows a planar Zn2O2 and (2)2 a planar Zn2N2 unit. Noteworthy, the aminal ring of 2,2‐dimethyl‐1,2,3,4‐tetrahydroquinazoline was opened by its reaction with diethylzinc to give an ylidene moiety at the benzylic nitrogen atom.

Synthesis, Protonation and CuII Complexes of Two Novel Isomeric Pentaazacyclophane Ligands: Potentiometric, DFT, Kinetic and AMP Recognition Studies

AbstractThe synthesis and coordination chemistry of two novel ligands, 2,6,9,12,16‐pentaaza[17]metacyclophane (L1) and 2,6,9,12,16‐pentaaza[17]paracyclophane (L2), is described. Potentiometric studies indicate that L1 and L2 form a variety of mononuclear complexes the stability constants of which reveal a change in the denticity of the ligand when moving from L1 to L2, a behaviour that can be qualitatively explained by the inability of the paracyclophanes to simultaneously use both benzylic nitrogen atoms for coordination to a single metal centre. In contrast, the formation of dinuclear hydroxylated complexes is more favoured for the para L2 ligand. DFT calculations have been carried out to compare the geometries and relative energies of isomeric forms of the [CuL]2+ complexes of L1 and L2 in which the cyclophane acts either as tri‐ or tetradentate. The results indicate that the energy cost associated with a change in the coordination mode of the cyclophane from tri‐ to tetradentate is moderate for both ligands so that the actual coordination mode can be determined not only by the characteristics of the first coordination sphere but also by the specific interactions with additional nearby water molecules. The kinetics of the acid promoted decomposition of the mono‐ and dinuclear CuII complexes of both cyclophanes have also been studied. For both ligands, dinuclear complexes convert rapidly to mononuclear species upon addition of excess acid, the release of the first metal ion occurring within the mixing time of the stopped‐flow instrument. Decomposition of the mononuclear [CuL2]2+ and [CuHL2]3+ species occurs with the same kinetics, thus showing that protonation of [CuL2]2+ occurs at an uncoordinated amine group. In contrast, the [CuL1]2+ and [CuHL1]3+ species show different decomposition kinetics indicating the existence of significant structural reorganisation upon protonation of the [CuL1]2+ species. The interaction of AMP with the protonated forms of the cyclophanes and the formation of mixed complexes in the systems Cu–L1‐AMP, Cu–L2‐AMP, and Cu–L3‐AMP, where L3 is the related pyridinophane containing the same polyamine chain and 2,6‐dimethylpyridine as a spacer, is also reported. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Comparative approaches toward diamines containing spatially separated homobenzylic and benzylic nitrogen stereocenters

Several synthetic strategies to diamines 1– 3 are described. The optimum approach via opening of aziridine afforded 1– 3 in 29–60% yield over 3–5 steps. A study on formation of the benzylic stereocenter using Toste’s rhenium-catalyzed asymmetric reduction of phosphinyl ketimines was also evaluated and afforded 15 in 92% de.

Design, Synthesis, and Biological Evaluation of Cyclic and Acyclic Nitrobenzylphosphoramide Mustards for E. coli Nitroreductase Activation

In efforts to obtain anticancer prodrugs for antibody-directed or gene-directed enzyme prodrug therapy using E. coli nitroreductase, a series of nitrobenzylphosphoramide mustards were designed and synthesized incorporating a strategically placed nitro group in a position para to the benzylic carbon for reductive activation. All analogues were good substrates of E. coli nitroreductase with half-lives between 2.9 and 11.9 min at pH 7.0 and 37 degrees C. Isomers of the 4-nitrophenylcyclophosphamide analogues 3 and 5 with a benzylic oxygen para to the nitro group showed potent selective cytotoxicity in nitroreductase (NTR) expressing cells, while analogues 4 and 6 with a benzylic nitrogen para to the nitro group showed little selective cytotoxicity despite their good substrate activity. These results suggest that good substrate activity and the benzylic oxygen are both required for reductive activation of 4-nitrophenylcyclophosphamide analogues by E. coli nitroreductase. Isomers of analogue 3 showed 23,000-29,000x selective cytotoxicity toward NTR-expressing V79 cells with an IC(50) as low as 27 nM. They are about as active as and 3-4x more selective than 5-aziridinyl-2,4-dinitrobenzamide (CB1954). The acyclic 4-nitrobenzylphosphoramide mustard ((+/-)-7) was found to be the most active and most selective compound for activation by NTR with 170,000x selective cytotoxicity toward NTR-expressing V79 cells and an IC(50) of 0.4 nM. Compound (+/-)-7also exhibited good bystander effect compared to 5-aziridinyl-2,4-dinitrobenzamide. The low IC(50), high selectivity, and good bystander effects of nitrobenzylphosphoramide mustards in NTR-expressing cells suggest that they could be used in combination with E. coli nitroreductase in enzyme prodrug therapy.

Protonation and coordination properties towards Zn(II), Cd(II) and Hg(II) of a phenanthroline-containing macrocycle with an ethylamino pendant arm.

Protonation and Zn(II), Cd(II) and Hg(II) coordination with the ligand 5-aminoethyl-2,5,8-triaza-[9]-10,23-phenanthrolinophane (L2), which contains an aminoethyl pendant attached to a phenanthroline-containing macrocycle, have been investigated by means of potentiometric, 1H NMR and spectrofluorimetric titrations in aqueous solutions. The coordination properties of L2 are compared with those of the ligand 2,5,8-triaza-[9]-10,23-phenanthrolinophane (L1). Ligand protonation occurs on the aliphatic amine groups and does not involve directly the heteroaromatic nitrogens. The fluorescence emission properties of L2 are controlled by the protonation state of the benzylic nitrogens: when not protonated, their lone pairs are available for an electron transfer process to the excited phenanthroline, quenching the emission. As a consequence, the ligand is emissive only in the highly charged [H3L2]3+ and [H4L2]4+ species, where the benzylic nitrogens are protonated. Considering metal complexation, both [ML1]2+ and [ML2]2+ complexes (M = Zn(II) and Cd(II)) are not emissive, since the benzylic nitrogens are weakly involved in metal coordination, and, once again, they are available for quenching the fluorescence emission. Protonation of the L2 complexes to give [MHL2]3+ species, instead, leads to a recovery of the fluorescence emission. Complex protonation, in fact, occurs on the ethylamino group and gives a marked change of the coordination sphere of the metals, with a stronger involvement in metal coordination of the benzylic nitrogens; consequently, their lone pairs are not available for the process of emission quenching.

X-RAY CRYSTAL AND MOLECULAR STRUCTURE OF AN ORGANOMETALLIC HYDRAZONE CONTAINING A ZIGZAG p-CONJUGATED SPACER: [CpFe(h6-C6H5)-N(Me)N=CH-C 6H4-4-NMe2]+ PF6-

The crystal and molecular structure of the complex [CpFe(h6-C6H5)-N(Me) N=CH-C6H4-4-NMe2] +PF6-, [1]+PF6-, was solved by single crystal X-ray diffraction analysis. One of the most salient features observed in this structure is the depyramidalization of both the benzylic nitrogen and the dimethylamino nitrogen atoms which reveals the delocalization of the p-electron system along the entire hydrazone skeleton from the donor to the acceptor termini, through a quinonoidal deformation and a pseudo-cyclohexadienyl conformation (folding dihedral angle of ca. 7.4°) of the free and coordinated phenyl rings, respectively. Both Cipso-N bond lengths are virtually identical (1.37 A), lying between pure single and double bonds. These and other peculiarities are described and compared with the structures of other organometallic hydrazones

First Case of Ring—Chain Tautomerism of N‐Unsubstituted 1,2,3,4‐Tetrahydroquinazolines.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Cu(ii) and Ni(ii) complexes with dipyridine-containing macrocyclic polyamines with different binding unitsElectronic supplementary information (ESI) available: selected bond lengths [Å] and angles [°] for [CuL1](ClO4)2 (Table S1) and for [NiL1](ClO4)2 (Table S2); absorption spectra of L2 in the presence of Cu(ii) (1 ∶ 1 molar ratio) at different pH values (Fig. S1). See http://www.rsc.org/suppdata/dt/b2/b211904h/

The coordination features of the two dipyridine-containing polyamine macrocycles 2,5,8,11,14-pentaaza[15]-[15](2,2′)[1,15]-bipyridylophane (L1) and 4,4′-(2,5,8,11,14-pentaaza[15]-[15](2,2′)-bipyridylophane) (L2) toward Cu(II) and Ni(II) have been studied by means of potentiometric and spectrophotometric UV-vis titrations in aqueous solutions. While in L1 all the nitrogen donor atoms are convergent inside the macrocyclic cavity, in L2 the heteroaromatic nitrogen atoms are located outside. Ligands L1 and L2 form stable mono- and dinuclear complexes with Cu(II). In the case of Ni(II) coordination, only L1 gives dinuclear complexes, while L2 can form only mononuclear species. In the Cu(II) or Ni(II) complexes with L1 the metal(s) are lodged inside the macrocyclic cavity, coordinated to the heteroaromatic nitrogens. As shown by the crystal structure of the [CuL1]2+ and [NiL1]2+ cations, at least one of the two benzylic nitrogens is not coordinated and facile protonation of the complex takes place at neutral or slightly acidic pH values. The particular molecular architecture of L2, which displays two well-separated binding moieties, strongly affects its coordination behavior. In the mononuclear [CuL2]2+ complex, the metal is encapsulated inside the cavity, not coordinated by the dipyridine unit. Protonation of the complex, however, occurs on the aliphatic polyamine chain and gives rise to translocation of the metal outside the cavity, bound to the heteroaromatic nitrogens. In the [NiL2]2+ complex the metal is coordinated by the dipyridine nitrogens, outside the macrocyclic cavity. Thermodynamic and/or kinetic considerations may explain the different behavior with respect to the corresponding Cu(II) complex.

Induction of Chirotopicity in the Self-Assembly Process of Heterocuprates: Structural and Stereochemical Aspects of Neutral CuLi2BrAryl2 Aggregates

Self-assembling reactions of the ortho-diamine chelated aryllithium dimers of type [Li(C∧N∧N‘)]2 with 1 equiv of CuBr resulted in the selective formation of hetero cuprates 1, 2, 3a, and 3b, respectively, which all have [CuLi2Br(C∧N∧N‘)2] stoichiometry (C∧N∧N‘ = Ar, [C6H4(CH2N(Me)CH2CH2NMe2)-2]- (1); Naph, [1-C10H6(CH2N(Me)CH2CH2NMe2)-2]- (2); (R)-Ar, (R)-[C6H4(CH(Me)N(Me)CH2CH2NMe2)-2]- (3a); or rac-Ar, rac-[C6H4(CH(Me)N(Me)CH2CH2NMe2)-2]- (3b)). The structure of 1 and 2 in the solid state comprises [(C∧N∧N‘)2Cu]- and [Li2Br]+ fragments which are joined by intramolecular N,N‘-chelation of the ortho-diamine ligand to lithium, thus forming an, overall neutral, 2:1 cuprate species. The coordinated benzylic nitrogen centers (NMe) in these trinuclear CuLi2 aggregates have a stable configuration, RN or SN. In fact, 1 and 2 exist in the solid state as RNRN and SNSN diastereoisomers, respectively. Accordingly, the halocuprates 1 and 2 can serve as model complexes for investigation of the structure of correspondi...

The synthesis of C2-symmetric 1,4,7-triazacyclononane ligands derived from chiral aziridines

An efficient synthetic route for the synthesis of C2-symmetric derivatives of 1,4,7-triazacyclononanes 14 from chiral pool amino acids has been developed. These investigations have shown that competitive formation of piperazines 7 occurs when inappropriate nitrogen protecting groups are employed. It is apparent that the formation of the piperazines occurs as a result of an intramolecular nucleophilic attack followed by a β-elimination. This appears to only be relevant for the formation of the [9]-N3 ring, as the larger [12]-N4 macrocycle, 11, is formed via a Richman–Atkins cyclisation in the presence of the same benzylic protected nitrogen atom. The single crystal X-ray structures of piperazine 7a and 1,4,7-triazacyclononanes 14a both reveal that weak intermolecular C–H⋯OS interactions occur in the solid state in these systems.

A new dipyridine-containing cryptand for both proton and Cu(ii) encapsulation. A solution and solid state study

Synthesis and characterization of the new polyamine cryptand 2,5,8-triaza-5-methyl-2,8-(N-methyldipropylamino)[9]-2,2′-dipyridinophane (L) and its macrocyclic precursor 2,5,8-triaza-5-methyl[9]-2,2′-dipyridinophane (L1) are reported. Ligand L1 contains a diethylenetriamine chain linking the 6,6′ positions of a 2,2′-dipyridine moiety; in L an N-methyldipropylamine bridge links the two benzylic nitrogens of L1. Protonation and Cu(II) coordination have been studied in aqueous solution by means of potentiometric and UV-vis spectrophotometric measurements. Considering proton binding, cryptand L behaves as a proton sponge, i.e., the first protonation constant is too high to be measured in aqueous solution. Both ligands form 1 ∶ 1 Cu(II) complexes in aqueous solutions. The crystal structure of [CuL1]2+ reveals that the metal is coordinated by the five ligand donors in a strongly distorted square pyramidal geometry. Almost the same coordination environment is found in the protonated complex with L, [CuLH]3+, while the nitrogen of the N-methyldipropylamine bridge is protonated. In marked contrast, in the [CuL]2+ complex this nitrogen is involved in metal coordination. Both the solution and structural results account for the high rigidity of the macrocyclic moiety of L defined by the dipyridine unit and the diethylenetriamine chain, while coordination of the more flexible N-methyldipropylamine unit is modulated by complex protonation.

First Case of Ring-Chain Tautomerism of N-Unsubstituted 1,2,3,4-Tetrahydroquinazolines

Goblyos et al. [1] have shown that ring–chain tautomerism is a characteristic feature of arylidene derivatives of 2-methylaminophenylamine with a substituent at the benzylic nitrogen atom. 1,2,3,4-Tetrahydroquinazoline structure has been assigned to the products of the reaction of aldehydes and ketones with 2-methylaminophenylamine [2, 3]. In previous work [4], we reported the tendency of imines of β-dicarbonyl compounds such as diketones, keto esters, and keto amides to exist as enamines. This suggested ring–chain tautomerism among the corresponding 2-methylaminophenylamine derivatives. In the present communication, we report the first example of such tautomerism A' . B for 3-(2-aminobenzylimino)-1-morpholin-4-yl-1-butanone (1), which is the product of the condensation of 2-methylaminophenylamine with acetoacetic acid morpholide. NMR spectral data indicate the instantaneous establishment of the A' . B equilibrium. The signal for sp-hybrid atom C(2) at 66.75 ppm serves as a characteristic feature for cyclic form B. Structure A should be eliminated due to the lack of a signal for the corresponding methylene group in the H NMR spectrum. All the signals of the linear form are in complete accord with structure A', which represents a cis isomer as indicated by NOE spectra. The nuclear Overhauser effect is observed for the signal of the C=C–H proton upon irradiation of the methyl protons, which indicates their cis orientation. Intramolecular hydrogen bonding between the NH proton and carbonyl group oxygen atom stabilizes the cis form. The nature of the solvent has a significant effect on the ratio of the tautomeric forms. The linear form predominates in DMSO-d6, while the ring form predominates in CDCl3. This phenomenon is well known for many tautomeric systems involving 1,3-dicarbonyl derivatives [4] (Scheme 1). We should note that the A' . B equilibrium differs fundamentally from the tautomerism of 1-substituted 2-methylaminophenylamines [1], in which the imine form participates at the anilinic nitrogen atom rather than the benzylic nitrogen atom. The NMR spectra were taken on a JEOL JNM-A-500 spectrometer. The H NMR spectra were taken at 500 MHz and the C NMR spectra were taken at 125 MHz, in DMSO-d6 at 30°C and in CDCl3 at 25°C. The 1D measurements involved NOE and determination of the major parameters of these spectra. The homonuclear H– H correlations involved the phase-sensitive DQF-COSY method, while the H–C heteronuclear correlations were determined by the HMQC method (for correlations through one bond, J1 = 145 MHz) and HMBC method (for correlations through two bonds, J2,3 = 8 Hz) with gradient selection. All the spectra were taken using standard pulse sequence sets.

Protonation and Zn(II) coordination by dipyridine-containing macrocycles with different molecular architecture. A case of pH-controlled metal jumping outside-inside the macrocyclic cavity.

The synthesis of the macrocyclic ligand 4,4'-(2,5,8,11,14-pentaaza[15])-2,2'-bipyridylophane (L3), which contains a pentaamine chain linking the 4,4'-positions of a 2,2'-dipyridine moiety, is reported. Protonation and Zn(II) complexation by L3 and by macrocycle L2, containing the same pentaamine chain connecting the 6,6'-positions of 2,2'-dipyridine, were studied by means of potentiometric, UV-vis, and fluorescent emission measurements. While in L2 all the nitrogen donor atoms are convergent inside the macrocyclic cavity, in L3 the heteroaromatic nitrogen atoms are located outside. Both ligands form mono- and dinuclear Zn(II) complexes in aqueous solution. In the mononuclear Zn(II) complexes with L2, the metal is coordinated inside the macrocyclic cavity, bound to the heteroaromatic nitrogen donors and three amine groups of the aliphatic chain. As shown by the crystal structure of the [ZnL2](2+) complex, the two benzylic nitrogens are not coordinated and facile protonation of the complex takes place at slightly acidic pH values. Considering the mononuclear [ZnL3](2+) complex, the metal is encapsulated inside the cavity, not coordinated by the dipyridine unit. Protonation of the complex occurs on the aliphatic polyamine chain and gives rise to translocation of the metal outside the cavity, bound to the heteroaromatic nitrogens.

Macrocyclic Polyamines Containing Phenanthroline Moieties – Fluorescent Chemosensors for H+ and Zn2+ Ions

The macrocyclic ligands L2 and L3, containing a triethylenetetraamine and a tetraethylenepentaamine moiety linked to the methyl groups of 2,9-dimethyl-1,10-phenanthroline, bind H+ and Zn2+ ions giving rise to modulation of the fluorescence emission intensity. The equilibrium constants and the enthalpy changes for ligand protonation were determined by means of pH-metric and microcalorimetric methods in 0.1 M Me4NCl solutions at 298.1±0.1 K. Also the stability constants of the Zn2+ complexes were determined under the same experimental conditions. L2 forms only mononuclear complexes, while L3 also forms dizinc(II) species. The phenanthroline group has fluorescence emission properties, but interaction with the lone pairs of benzylic nitrogen atoms produces an efficient quenching of the emission. Such a quenching effect can be avoided by deactivation of the benzylic nitrogen atoms by means of protonation or Zn2+ complexation. Hence, L2 and L3 behave as chemosensor for H+ and Zn2+, the photochemical properties of the ligands being modulated by the formation of different protonated and complexed species. In the case of L3, the fluorescence emission is also controlled by the metal to ligand molar ratio, because of the formation of an emissive binuclear complex.

Guest-Induced Selective Functionalization of Polyaza[n]paracyclophanes

A new strategy to the preparation of selectively functionalized polyazamacrocycles is presented. Polyaza[n]paracyclophane receptors are able to efficiently direct their own selective functionalization upon interaction with simple guests such as metal cations. This enables the preparation of novel receptors functionalized at one of the benzylic nitrogen atoms with a variety of groups. Selective difunctionalization at both benzylic positions can also be achieved in this way.

Outer and inner coordination sphere chemistry of polyazacyclophane platinum(II) complexes. Crystal structure of [PtBr4]2(H4L1) · H2O (L1 = 2,6,9,13-tetraaza[14]paracyclophane)

The interaction of PtCl42− with the new azaparacyclophane 2,5,8,11-tetraaza[12]paracyclophane (L2) has been studied by 1H, 13C and 195Pt NMR spectroscopy. Three different complexes are detected as a function of pH, all of them presenting cis-arrangement of nitrogen donors and chloride anions. In the first one, formed at acidic pH, the central nitrogen atoms of the macrocyclic are coordinating to Pt(II) while the benzylic nitrogens remain protonated. Deprotonation of these nitrogens brings about a reorganisation of the complex, and the platinum is then coordinated by one benzylic nitrogen and the consecutive nitrogen in the macrocycle. This process can be monitored by NMR. Finally, addition of a second mol of PtCl42− for each mole of L2 causes, most likely, the formation of a binuclear complex in which the tetrammine chain behaves as two ethylenediamine subunits. The crystal structure of the adduct [PtBr4]2[H4L1] has been solved by X-ray diffraction analysis (space group P21/c, a = 8.092(2), b = 16.049(2), c = 21.783(3) Å, α = 90.00(1), β = 100.34(2), γ = 90.00(1), Z = 4, R1 = 0.0528, wR2 = 0.1612). The compound is held together mainly through coulombic interactions between the charged polyammonium groups of the macrocycle and the PtBr42− anions aswell as through an extensive hydrogen bond network in which participate the bromides of the two PtBr42− anions and a lattice water molecule.

Chemoselective debenzylation involving removal of a 2-hydroxy-1-phenylethyl group from nitrogen

In 2-(2-hydroxy-1-phenylethyl)-1-isoindolinone, selective removal of the 2-hydroxy-1-phenylethyl group is convenienthyl achieved via a 3-step sequence (mesylation, elimination, hydrolysis) without breaking an endocyclic benzylic nitrogen bond.