Direct, Stereodivergent, and Catalytic Michael Additions of Thioimides to α,ß-Unsaturated Aldehydes - Total Synthesis of Tapentadol.

Direct and stereodivergent Michael additions of N-acyl 1,3-thiazinane-2-thiones to α,ß-unsaturated aldehydes catalyzed by chiral nickel(II) complexes are reported. The reactions proceed with a remarkable regio-, diastereo-, and enantioselectivity, so access to any of the four potential Michael stereoisomers is granted through the appropriate choice of the chiral ligand of the nickel(II) complex. Simple removal of the heterocyclic scaffold furnishes a wide array of either syn or anti enantiomerically pure derivatives, which can be exploited for the asymmetric synthesis of biologically active compounds, as demonstrated in a new approach to tapentadol. In turn, a mechanism, based on theoretical calculations, is proposed to account for the stereochemical outcome of these transformations.

Cyclic Homo- and Heterohalogen Di-λ3-diarylhalonium Structures.

In the context of the ever-growing interest in the cyclic diaryliodonium salts, this work presents synthetic design principles for a new family of structures with two hypervalent halogens in the ring. The smallest bis-phenylene derivative, [(C6H4)2I2]2+, was prepared through oxidative dimerization of a precursor bearing the ortho-disposed iodine and trifluoroborate groups. We also report, for the first time, the formation of cycles containing two different halogen atoms. These present two phenylenes linked by hetero-(I/Br) or -(I/Cl) halogen pairs. This approach was also extended to the cyclic bis-naphthylene derivative [(C10H6)2I2]2+. The structures of these bis-halogen(III) rings were further assessed through X-ray analysis. The simplest cyclic phenylene bis-iodine(III) derivative features the interplanar angle of ∼120°, while a smaller angle of ∼103° was found for the analogous naphthylene-based salt. All dications form dimeric pairs through a combination of π-π and C-H/π interactions. As the largest member of the family, a bis-I(III)-macrocycle was also assembled using the quasi-planar xanthene backbone. Its geometry enables the two iodine(III) centers to be bridged intramolecularly by two bidentate triflate anions. In a preliminary manner, the interaction of the phenylene- and naphthalene-based bis-iodine(III) dications with a new family of rigid bidentate bis-pyridine ligands was studied in solution and the solid state, with an X-ray structure showing the chelating donor bonding to just one of the two iodine centers.

Slow Magnetic Relaxation in Silver(II) Macrocyclic Systems.

The spin-lattice relaxation time has been studied trough alternating-current susceptometry and ultralow-frequency Raman spectroscopy in a family of silver(II)-derived molecular systems with spin 1/2 and formulas [AgII(m-CTH)(NO3)2] (1) and [AgII(m-CTH)(ClO4)2] (2), where CTH = meso-5,5,7,12,12,14-hexamethyl-1,4,8,11-tetraazacyclotetradecane. The combination of both techniques demonstrates the occurrence of slow spin magnetic relaxation induced by spin-phonon interaction. The magnetic behavior of these silver(II)-derived systems opens the door to a new cation in the scarce family of S = 1/2 systems with slow relaxation of magnetization.

Direct and Asymmetric Aldol Reactions of N-Azidoacetyl-1,3-thiazolidine-2-thione Catalyzed by Chiral Nickel(II) Complexes. A New Approach to the Synthesis of ß-Hydroxy-α-Amino Acids.

A direct and asymmetric triisopropylsilyltrifluoromethanesulfonate (TIPSOTf) mediated aldol reaction of N-azidoacetyl-1,3-thiazolidine-2-thione with aromatic aldehydes catalyzed by a chiral nickel(II)-Tol-BINAP complex has been developed (BINAP=2,2'-bis(diphenylphosphino)-1,1'-binaphthyl). The catalytic protocol gives the corresponding anti α-azido-ß-silyloxy adducts with outstanding stereocontrol and in high yields. Theoretical calculations account for the stereochemical outcome of the reaction and lay the foundations for a mechanistic model. In turn, the easy removal of the thiazolidinethione yields a wide array of enantiomerically pure derivatives in a straightforward and efficient manner. Such a noteworthy character of the heterocyclic scaffold together with the appropriate manipulation of the azido group open a new route to the synthesis of di- and tripeptide blocks containing a ß-aryl-ß-hydroxy-α-amino acid.

Controlling the Formation of Two Concomitant Polymorphs in Hg(II) Coordination Polymers.

Controlling the formation of the desired product in the appropriate crystalline form is the fundamental breakthrough of crystal engineering. On that basis, the preferential formation between polymorphic forms, which are referred to as different assemblies achieved by changing the disposition or arrangement of the forming units within the crystalline structure, is one of the most challenging topics still to be understood. Herein, we have observed the formation of two concomitant polymorphs with general formula {[Hg(Pip)2(4,4'-bipy)]·DMF}n (P1A, P1B; Pip = piperonylic acid; 4,4'-bipy = 4,4'-bipyridine). Besides, [Hg(Pip)2(4,4'-bipy)]n (2) has been achieved during the attempts to isolate these polymorphs. The selective synthesis of P1A and P1B has been successfully achieved by changing the synthetic conditions. The formation of each polymorphic form has been ensured by unit cell measurements and decomposition temperature. The elucidation of their crystal structure revealed P1A and P1B as polymorphs, which originates from the Hg(II) cores and intermolecular associations, especially pinpointed by Hg···π and π···π interactions. Density functional theory (DFT) calculations suggest that P1B, which shows Hg(II) geometries that are further from ideality, is more stable than P1A by 13 kJ·mol-1 per [Hg(Pip)2(4,4'-bipy)]·DMF formula unit, and this larger stability of P1B arises mainly from metal···π and π···π interactions between chains. As a result, these structural modifications lead to significant variations of their solid-state photoluminescence.

Tuning Photophysical Properties by p-Functional Groups in Zn(II) and Cd(II) Complexes with Piperonylic Acid.

Aggregation between discrete molecules is an essential factor to prevent aggregation-caused quenching (ACQ). Indeed, functional groups capable of generating strong hydrogen bonds are likely to assemble and cause ACQ and photoinduced electron transfer processes. Thus, it is possible to compare absorption and emission properties by incorporating two ligands with a different bias toward intra- and intermolecular interactions that can induce a specific structural arrangement. In parallel, the π electron-donor or electron-withdrawing character of the functional groups could modify the Highest Ocuppied Molecular Orbital (HOMO)-Lowest Unocuppied Molecular Orbital (LUMO) energy gap. Reactions of M(OAc)2·2H2O (M = Zn(II) and Cd(II); OAc = acetate) with 1,3-benzodioxole-5-carboxylic acid (Piperonylic acid, HPip) and 4-acetylpyridine (4-Acpy) or isonicotinamide (Isn) resulted in the formation of four complexes. The elucidation of their crystal structure showed the formation of one paddle-wheel [Zn(µ-Pip)2(4-Acpy)]2 (1); a mixture of one dimer and two monomers [Zn(µ-Pip)(Pip)(Isn)2]2·2[Zn(Pip)2(HPip)(Isn)]·2MeOH (2); and two dimers [Cd(µ-Pip)(Pip)(4-Acpy)2]2 (3) and [Cd(µ-Pip)(Pip)(Isn)2]2·MeOH (4). They exhibit bridged (1, µ2-η1:η1), bridged, chelated and monodentated (2, µ2-η1:η1, µ1-η1:η1 and µ1-η1), or simultaneously bridged and chelated (3 and 4, µ2-η2:η1) coordination modes. Zn(II) centers accommodate coordination numbers 5 and 6, whereas Cd(II) presents coordination number 7. We have related their photophysical properties and fluorescence quantum yields with their geometric variations and interactions supported by TD-DFT calculations.

Magnetic and Luminescence Properties of 8-Coordinate Holmium(III) Complexes Containing 4,4,4-Trifluoro-1-Phenyl- and 1-(Naphthalen-2-yl)-1,3-Butanedionates.

A new series of mononuclear Ho3+ complexes derived from the ß-diketonate anions: 4,4,4-trifluoro-1-phenyl-1,3-butanedioneate (btfa-) and 4,4,4-trifuoro-1-(naphthalen-2-yl)-1,3-butanedionate (ntfa-) have been synthesized, [Ho(btfa)3(H2O)2] (1a), [Ho(ntfa)3(MeOH)2] (1b), (1), [Ho(btfa)3(phen)] (2), [Ho(btfa)3(bipy)] (3), [Ho(btfa)3(di-tbubipy)] (4), [Ho(ntfa)3(Me2bipy)] (5), and [Ho(ntfa)3(bipy)] (6), where phen is 1,10-phenantroline, bipy is 2,2'-bipyridyl, di-tbubipy is 4,4'-di-tert-butyl-2,2'-bipyridyl, and Me2bipy is 4,4'-dimethyl-2,2'-bipyridyl. These compounds have been characterized by elemental microanalysis and infrared spectroscopy as well as single-crystal X-ray difraction for 2-6. The central Ho3+ ions in these compounds display coordination number 8. The luminescence-emission properties of the pyridyl adducts 2-6 display a strong characteristic band in the visible region at 661 nm and a series of bands in the NIR region (excitation wavelengths (λex) of 367 nm for 2-4 and 380 nm for 5 and 6). The magnetic properties of the complexes revealed magnetically uncoupled Ho3+ compounds with no field-induced, single-molecule magnet (SMMs).

Single-Ion Anisotropy and Intramolecular Interactions in CeIII and NdIII Dimers.

This article reports the syntheses, characterization, structural description, together with magnetic and spectroscopic properties of two isostructural molecular magnets based on the chiral ligand N,N'-bis((1,2-diphenyl-(pyridine-2-yl)methylene)-(R,R/S,S)-ethane-1,2-diamine), L1, of general formula [Ln2(RR-L1)2(Cl6)]·MeOH·1.5H2O, (Ln = Ce (1) or Nd (2)). Multifrequency electron paramagnetic resonance (EPR), cantilever torque magnetometry (CTM) measurements, and ab initio calculations allowed us to determine single-ion magnetic anisotropy and intramolecular magnetic interactions in both compounds, evidencing a more important role of the anisotropic exchange for the NdIII derivative. The comparison of experimental and theoretical data indicates that, in the case of largely rhombic lanthanide ions, ab initio calculations can fail in determining the orientation of the weakest components, while being reliable in determining their principal values. However, they remain of paramount importance to set the analysis of EPR and CTM on sound basis, thus obtaining a very precise picture of the magnetic interactions in these systems. Finally, the electronic structure of the two complexes, as obtained by this approach, is consistent with the absence of zero-field slow relaxation observed in ac susceptibility.

Steric and Electronic Effects on the Structure and Photophysical Properties of Hg(II) Complexes.

Since many factors influence the coordination around a metal center, steric and electronic effects of the ligands mainly determine the connectivity and, thus, the final arrangement. This is emphasized on Hg(II) centers, which have a zero point stabilization energy and, thus, a flexible coordination environment. Therefore, the unrestricted Hg(II) geometry facilitates the predominance of the ligands during the structural inception. Herein, we synthesized and characterized a series of six Hg(II) complexes with general formula (Hg(Pip)2(dPy)) (Pip = piperonylate, dPy = 3-phenylpyridine (3-phpy) (1), 4-phenylpyridine (4-phpy) (2), 2,2'-bipyridine (2,2'-bipy) (3), 1,10-phenanthroline (1,10-phen) (4), 2,2':6',2'-terpyridine (terpy) (5), or di(2-picolyl)amine (dpa) (6)). The elucidation of their crystal structures revealed the arrangement of three monomers (3, 5, and 6), one dimer (4), and two coordination polymers (1 and 2) depending on the steric requirements of the dPy and predominance of the ligands. Besides, the study of their photophysical properties in solution supported by TD-DFT calculations enabled us to understand their electronic effects and the influence of the structural arrangement on them.

Molecular Approach to Alkali-Metal Encapsulation by a Prussian Blue Analogue FeII/CoIII Cube in Aqueous Solution: A Kineticomechanistic Exchange Study.

The preparation of a series of alkali-metal inclusion complexes of the molecular cube [{CoIII(Me3-tacn)}4{FeII(CN)6}4]4- (Me3-tacn = 1,4,7-trimethyl-1,4,7-triazacyclononane), a mixed-valent Prussian Blue analogue bearing bridging cyanido ligands, has been achieved by following a redox-triggered self-assembly process. The molecular cubes are extremely robust and soluble in aqueous media ranging from 5 M [H+] to 2 M [OH-]. All the complexes have been characterized by the standard mass spectometry, UV-vis, inductively coupled plasma, multinuclear NMR spectroscopy, and electrochemistry. Furthermore, X-ray diffraction analysis of the sodium and lithium salts has also been achieved, and the inclusion of moieties of the form {M-OH2}+ (M = Li, Na) is confirmed. These inclusion complexes in aqueous solution are rather inert to cation exchange and are characterized by a significant decrease in acidity of the confined water molecule due to hydrogen bonding inside the cubic cage. Exchange of the encapsulated cationic {M-OH2}+ or M+ units by other alkali metals has also been studied from a kineticomechanistic perspective at different concentrations, temperatures, ionic strengths, and pressures. In all cases, the thermal and pressure activation parameters obtained agree with a process that is dominated by differences in hydration of the cations entering and exiting the cage, although the size of the portal enabling the exchange also plays a determinant role, thus not allowing the large Cs+ cation to enter. All the exchange substitutions studied follow a thermodynamic sequence that relates with the size and polarizing capability of the different alkali cations; even so, the process can be reversed, allowing the entry of {Li-OH2}+ units upon adsorption of the cube on an anion exchange resin and subsequent washing with a Li+ solution.

Direct and Enantioselective Aldol Reactions Catalyzed by Chiral Nickel(II) Complexes.

A direct and asymmetric aldol reaction of N-acyl thiazinanethiones with aromatic aldehydes catalyzed by chiral nickel(II) complexes is reported. The reaction gives the corresponding O-TIPS-protected anti-aldol adducts in high yields and with remarkable stereocontrol and atom economy. Furthermore, the straightforward removal of the achiral scaffold provides enantiomerically pure intermediates of synthetic interest, which involve precursors for anti-α-amino-ß-hydroxy and α,ß-dihydroxy carboxylic derivatives. Theoretical calculations explain the observed high stereocontrol.

From Bowls to Capsules: Assembly of Hexanuclear NiII Rings Tailored by Alkali Cations.

An anionic hexanuclear NiII metallamacrocycle with endo and exo linking sites has been employed as a building block to generate a series of capsules and bowls of nanometric size. The supramolecular arrangement of the {Ni6 } rings was tailored by the size of the alkali cations, showing the transition from {Ni6 -M2 -Ni6 } capsules (M=LiI and NaI ) to {Ni6 -M} bowls (M=KI and CsI ). The alkyl co-cations are determinant to stabilize the assemblies by means of CH⋅⋅⋅π interactions on the exo side of the metallamacrocycles. The effect on the topology of the supramolecular assemblies of the cation size, cation charge, Et3 NH+ or Me4 N+ counter cations has been analyzed. Magnetic measurements reveal the presence of ferromagnetic and antiferromagnetic interactions inside the rings that allow a S=0 ground state.

Chiral Versus Non-Chiral [MnIII 6 MnII NaI ], [MnIII 6 MnII 2 NaI 2 ] and [MnIII 3 MnII NaI ] Clusters Derived from Schiff Bases or the Fight for Symmetry.

The reaction in basic media of manganese chloride with Schiff bases derived from the condensation of o-vanillin with different chiral/racemic aminoalcohols yielded in a family of complexes in which the nuclearity, symmetry and magnetic behavior is controlled by changing the position of the chiral carbon. Chiral and racemic clusters with [MnIII 6 MnII NaI ], [MnIII 6 MnII 2 NaI 2 ] and [MnIII 3 MnII NaI ] metallic core have been structurally and magnetically characterized. The racemic clusters with an odd number of chiral ligands exhibit the anomalous mixing of ligands with different conformation. Related racemic compounds have been reviewed.

Direct, Enantioselective, and Nickel(II) Catalyzed Reactions of N-Azidoacetyl Thioimides with Trimethyl Orthoformate: A New Combined Methodology for the Rapid Synthesis of Lacosamide and Derivatives.

A direct and highly enantioselective reaction of N-azidoacetyl-1,3-thiazolidine-2-thione with trimethyl orthoformate catalyzed by Tol-BINAPNiCl2 in the presence of TESOTf and 2,6-lutidine is reported. The heterocyclic scaffold can be easily removed by addition of a wide array of amines to give the corresponding enantiomerically pure 2-azido-3,3-dimethoxypropanamides in high yields. Appropriate manipulation of the N-benzyl amide derivative provides an efficient access to the antiepileptic agent lacosamide through a new enantioselective C-C bond-forming process. DFT computational studies uncover clues for the understanding of the remarkable stereocontrol of the addition of a nickel(II) enolate to a putative oxocarbenium intermediate from trimethyl orthoformate.

Luminescent PtII and PtIV Platinacycles with Anticancer Activity Against Multiplatinum-Resistant Metastatic CRC and CRPC Cell Models.

Platinum-based chemotherapy persists to be the only effective therapeutic option against a wide variety of tumours. Nevertheless, the acquisition of platinum resistance is utterly common, ultimately cornering conventional platinum drugs to only palliative in many patients. Thus, encountering alternatives that are both effective and non-cross-resistant is urgent. In this work, we report the synthesis, reduction studies, and luminescent properties of a series of cyclometallated (C,N,N')PtIV compounds derived from amine-imine ligands, and their remarkable efficacy at the high nanomolar range and complete lack of cross-resistance, as an intrinsic property of the platinacycle, against multiplatinum-resistant colorectal cancer (CRC) and castration-resistant prostate cancer (CRPC) metastatic cell lines generated for this work. We have also determined that the compounds are effective and selective for a broader cancer panel, including breast and lung cancer. Additionally, selected compounds have been further evaluated, finding a shift in their antiproliferative mechanism towards more cytotoxic and less cytostatic than cisplatin against cancer cells, being also able to oxidize cysteine residues and inhibit topoisomerase II, thereby holding great promise as future improved alternatives to conventional platinum drugs.

A captured room temperature stable Wheland intermediate as a key structure for the orthogonal decoration of 4-amino-pyrido[2,3-d]pyrimidin-7(8H)-ones.

Wheland intermediates are usually unstable compounds and only a few have been isolated at very low temperatures. During our work on tyrosine kinase inhibitors, we studied the bromination of 7 in order to obtain a dibromo substituted pyrido[2,3-d]pyrimidin-7(8H)-one which could be orthogonally decorated. Surprisingly, treatment of 7 with 3 equiv. of Br2 in acetic acid (AcOH) afforded 12, a captured room temperature stable Wheland bromination intermediate stabilized by the bromination of the imino tautomer of the amino group at C4 of the pyridopyrimidine skeleton. The structure was confirmed by crystal structure determination from powder X-ray diffraction data. Treatment of 12 with DMSO afforded the dibromo substituted compound 13 presenting a bromine atom at C6 and C5-C6 unsaturation. 13 was directly accessed by treating 7 with N-bromosuccinimide (NBS), a protocol extended to other compounds using NBS or N-iodosuccinimide (NIS) to afford 6-halo substituted systems. 26, bearing an iodine at C6 and a p-bromophenylamino at C2, allows the orthogonal decoration of pyridopyrimidines.

C4-C5 fused pyrazol-3-amines: when the degree of unsaturation and electronic characteristics of the fused ring controls regioselectivity in Ullmann and acylation reactions.

Pyrazol-3-amine is a scaffold present in a large number of compounds with a wide range of biological activities and, in many cases, the heterocycle is C4-C5 fused to a second ring. Among the different reactions used for the decoration of the pyrazole ring, Ullmann and acylation have been widely applied. However, there is some confusion in the literature regarding the regioselectivity of such reactions (substitution at N1 or N2 of the pyrazole ring) and no predictive rule has been so far established. As a part of our work on 3-amino-pyrazolo[3,4-b]pyridones 13, we have studied the regioselectivity of such reactions in different C4-C5 fused pyrazol-3-amines. As a rule of thumb, the Ullmann and acylation reactions take place, predominantly, at the NH and non-protonated nitrogen atom of the pyrazole ring respectively, of the most stable initial tautomer (1H- or 2H-pyrazole), which can be easily predicted by using DFT calculations.

Construction of Zn(II) Linear Trinuclear Secondary Building Units from A Coordination Polymer Based on α-Acetamidocinnamic Acid and 4-Phenylpyridine.

The synthesis and characterization of one coordination polymer and two trinuclear complexes are presented. The coordination polymer [Zn2(µ-O,O'-ACA)2(ACA)2(4-Phpy)2]n (1) has been obtained by the reaction between Zn(OAc)2·2H2O, α-acetamidocinnamic acid (HACA), and 4-phenylpyridine (4-Phpy) using EtOH as solvent. Its recrystallization in CH3CN or EtOH yields two trinuclear complexes, both having pinwheel arrays with formulas [Zn3(µ-ACA)6(4-Phpy)2]·4CH3CN (2·4CH3CN) and [Zn3(µ-ACA)6(EtOH)2]·4EtOH (3·4EtOH), respectively. These trinuclear species, unavoidably lose their solvent co-crystallized molecules at RT yielding the complexes [Zn3(µ-ACA)6(4-Phpy)2] (2) and [Zn3(µ-ACA)6(EtOH)2] (3). In addition, compound 2 has also been obtained reacting Zn(OAc)2·2H2O, HACA, and 4-Phpy in a 1:2:2 ratio using CH3CN as solvent. Compounds 1-3 have been characterized by analytical and spectroscopic techniques. Furthermore, single crystals suitable for X-ray diffraction method for compounds 1, 2·4CH3CN, and 3·4EtOH were obtained and their supramolecular interactions have been studied and discussed, showing 2D supramolecular planes for the trinuclear complexes and a 3D supramolecular network for the coordination polymer. Finally, the supramolecular interactions of 2·4CH3CN and 3·4EtOH have been compared using Hirshfeld surface analysis and electrostatic potential calculations.

Isonicotinamide-Based Compounds: From Cocrystal to Polymer.

The reaction between [Cu(µ-OAc)(µ-Pip)(MeOH)]2 (1) (OAc = acetate; Pip = 1,3-benzodioxole-5-carboxylate) and isonicotinamide (Isn) in MeOH as solvent yielded two mixture pairs of three compounds: {(HPip)2(Isn) (2), [Cu(Pip)2(Isn)2] (3)} and {(3), {[Cu3(Pip)2(OAc)2(µ-Isn)2(Isn)2(µ-OCH3)2(MeOH)2]·2MeOH}n (4)}. Modifying the reaction conditions (t, T, molar ratio), 2 and 3 have been successfully isolated, whereas 3 and 4 had to be mechanically separated. The recrystallization of 3 in pentanol yielded single crystals of compound [Cu(Pip)2(Isn)2]·C5H11OH (3a). The X-ray crystal structure of 2, 3a, and 4 has been elucidated showing a cocrystal, a monomer, and an unusual coordination polymer, respectively. The Pip ligand exhibited a chelate (3a) or a monodentate (4) coordination mode, but the Isonicotinamide (Isn) ligand is the one that promoted the arrangement of different structures and also mainly directs the formation of the 2D and 3D supramolecular assemblies. All the structures have been analyzed by Hirshfeld surface. In addition, the energy frameworks and lattice energy values of 2 and 3a have been calculated.

Chiral [MnII MnIII 3 M'] (M'=NaI , CaII , MnII ) and [MnII MnIII 6 NaI 2 ] Clusters Built from an Enantiomerically Pure Schiff Base: Synthetic, Chiroptical, and Magnetic Properties.

From the reaction of manganese halides with the chiral Schiff bases obtained by condensation of o-vanillin and (R)- or (S)-phenylglycinol, 11 complexes based on pentanuclear cages with trigonal bipyramidal [MnII MnIII 3 M'] (M'=NaI , CaII , MnII ) or enneanuclear [MnII MnIII 6 NaI 2 ] cores were synthesized. Structural, supramolecular chirality, and optical properties were explored. The magnetic properties of related systems were reviewed, and the magnetic response of the new systems was rationalized to the bond parameters.