Synthesis of the Marine Alkaloid Cylindricine C and Serendipitous Synthesis of Its 2,13-Di-epi Stereoisomer.

A new approach to the marine alkaloid cylindricine C afforded its previously unreported (±)-2,13-di-epi stereoisomer as the major product along with a minor amount of the racemic parent alkaloid. Key steps included a stereoselective dianion alkylation of a monoester of 1,2-cyclohexanedicarboxylic acid and an annulation based on the tandem conjugate addition of a primary amine to an acetylenic sulfone, followed by intramolecular acylation of the resulting sulfone-stabilized carbanion. The cis-azadecalin moiety thus formed, comprising the cyclohexane A-ring and enaminone B-ring of the products, was further elaborated by the selenenyl chloride-induced cyclofunctionalization of a pendant butenyl substituent with the enaminone moiety, followed by a seleno-Pummerer reaction. Desulfonylation and enaminone reduction afforded the final products. Molecular modeling and X-ray crystallography provided further insight into these processes.

Generation of Benzyne Species from Diphenylphosphoryl Derivatives: Simultaneous Exchange of Three Functional Groups.

Interaction of (2-diphenylphosphoryl-3-iodo-4-methoxy-phenyl) methanol with NaH in DMF at ambient temperature results in the generation of benzyne intermediates that can be trapped by furan or DMF. Trapping with DMF forms 3-(dimethylaminomethyl)-2-hydroxy-6-methoxybenzaldehyde demonstrating the simultaneous exchange of three functionalities in a single step. The presence of the alkoxy substituent adjacent to iodine is critical for high regioselectivity addition of DMF. The corresponding bromide or triflate can be used in place of the iodide with equal efficiency. This methodology was used to synthesize the reported structure of gigasol and leading to a structural reassignment of this biscoumarin natural product.

Photo Lewis acid generators: photorelease of B(C6F5)3 and applications to catalysis.

A series of molecules capable of releasing of the strong organometallic Lewis acid B(C6F5)3 upon exposure to 254 nm light have been developed. These photo Lewis acid generators (PhLAGs) can now serve as photoinitiators for several important B(C6F5)3-catalyzed reactions. Herein is described the synthesis of the triphenylsulfonium and diphenyliodonium salts of carbamato- and hydridoborates, their establishment as PhLAGs, and studies aimed at defining the mechanism of borane release. Factors affecting these photolytic reactions and the application of this concept to photoinduced hydrosilylation reactions and construction of siloxane scaffolds are also discussed.

Ammonia Activation by a Nickel NCN-Pincer Complex featuring a Non-Innocent N-Heterocyclic Carbene: Ammine and Amido Complexes in Equilibrium.

A Ni(0)-NCN pincer complex featuring a six-membered N-heterocyclic carbene (NHC) central platform and amidine pendant arms was synthesized by deprotonation of its Ni(II) precursor. It retained chloride in the square-planar coordination sphere of nickel and was expected to be highly susceptible to oxidative addition reactions. The Ni(0) complex rapidly activated ammonia at room temperature, in a ligand-assisted process where the carbene carbon atom played the unprecedented role of proton acceptor. For the first time, the coordinated (ammine) and activated (amido) species were observed together in solution, in a solvent-dependent equilibrium. A structural analysis of the Ni complexes provided insight into the highly unusual, non-innocent behavior of the NHC ligand.

Anti-HIV activity of new pyrazolobenzothiazine 5,5-dioxide-based acetohydrazides.

A series of fifteen new 2-[3-(3-chlorophenyl)-5,5-dioxidobenzo[e]pyrazolo[4,3-c][1,2]thiazin-4(2H)-yl]-N'-arylmethyleneacetohydrazides (5a-o) were synthesized and screened for their anti-HIV-1 and cytotoxicity activity. Out of fifteen pyrazolobenzothiazine-based hydrazones, thirteen were found to be active inhibitors of HIV with EC50 values <20 µM. Moreover, the cytotoxicity results showed that most of the compounds were toxic to PBM, CEM and Vero cell lines. This information could be used for structural modifications to acquire good candidates of HIV drugs.

Silver ion enhanced C-H activation in Pt(II) hydroxo complexes.

Reacting neutral Pt(ii) hydroxo compounds (NN)Pt(R)(OH) (R = OH, Ph, and Me, NN = bulky terphenyl diimine) with silver bis(trifluromethanesulfonyl)imide produces new hydroxo complexes with the silver binding through the Pt-OH bonds as determined by (195)Pt NMR and X-ray analysis (R = OH). These complexes were found to activate the aromatic C-D bonds of C6D6 at significantly enhanced rates relative to the silver free hydroxo complexes. Mechanistic studies for R = Ph are consistent with a homogeneous pathway that is bimolecular (ΔH(‡) = 17(2) kcal mol(-1) and ΔS(‡) = -25(6) e.u. and ΔG = 10(2) kcal mol(-1)), first order in [Pt] and substrate.

Reversible interconversion between a monomeric iridium hydroxo and a dinuclear iridium µ-oxo complex.

Treatment of the (PCsp(2)P)Ir(I)Cl complexes 2(R) (R = (i)Pr, (t)Bu) with cesium hydroxide in THF leads to the corresponding monomeric Ir(I) hydroxo complexes 5(R) in good to excellent yields of 70% (R = (i)Pr) and 92% (R = (t)Bu). The compounds are green in color and while they exhibit very similar (31)P NMR data to the chlorides 2, the (1)H NMR spectrum of each features a triplet ((3)JHP = 3.8 Hz) at 4.22 (R = (t)Bu) and 4.31 (R = (i)Pr) ppm that broadens in the presence of excess water and exchanges deuterium with D2O. Bands at 3642 and 3625 cm(-1) are observed in the IR spectrum for the νOH stretch. In the case of R = (i)Pr, a second product is observed in the crude reaction mixture and dominates when 5((i)Pr) is heated under vacuum and H2O is removed. This product is deep blue in color, and an X-ray crystal structure analysis reveals it to be the S4 symmetric dinuclear (PCsp(2)P)Ir-O-Ir(PCsp(2)P) complex 6((i)Pr), which features a µ-oxo ligand along an allene-like molecular core. Time-dependent DFT calculations with the M06 density functional show that a metal-to-ligand HOMO-LUMO excitation is mainly responsible for the blue color. Upon reaction of 6((i)Pr) with water, monomeric hydroxo complex 5((i)Pr) is quantitatively regenerated. Further, reaction of 6((i)Pr) with an excess of phenol smoothly yields the previously prepared (PCsp(2)P)IrOPh complex 3((i)Pr). Kinetic studies of the reaction indicated that it is first order in both [6((i)Pr)] and [HOPh] and exhibits a kH/kD of 1.9 when DOPh is employed. Eyring analysis is consistent with the bimolecular nature of the reaction, with ΔH(‡) = 13.1(5) kcal mol(-1) and ΔS(‡) = -13(2) cal K(-1). Finally, kobs is observed to increase when electron-withdrawing groups are incorporated in the para position of the phenol substrate and decrease when electron-donating groups are employed. These observations suggest that the rate-limiting step in this reaction is protonation of the µ-oxo ligand by the phenol substrate. This reaction serves as a model system for the reversible condensation of metal hydroxo ligands to form metal oxo moieties.

Selective hydrosilation of CO2 to a bis(silylacetal) using an anilido bipyridyl-ligated organoscandium catalyst.

A rigid anilido bipyridyl ligand has been designed for use in an organoscandium-based carbon dioxide hydrosilation catalyst. Ligand attachment by alkane elimination results in metalation of an aryl C-H bond in a 3,5-di-tert-butylphenyl group installed on the pyridyl unit, thus rendering the ligand tetradentate. Insertion of CO2 into the newly formed Sc-C bond leads to a κ(1) carboxylate which, when treated with the borane B(C6F5)3, becomes hemilabile. In addition to activating the catalyst, the k(1) carboxylate effectively sequesters free B(C6F5)3 and the ensemble is able to effectively hydrosilate CO2, in the presence of excess Et3SiH, almost exclusively to R3SiOCH2OSiR3. A maximum turnover number of about 3400 (conversion of silane) is observed. Mechanistic experiments suggest that the sequestration of free B(C6F5)3 by the hemilabile carboxylate contributes to the selectivity observed and prevents over reduction to methane.

Synthesis and anti-HIV-1 screening of novel N'-(1-(aryl)ethylidene)-2-(5,5-dioxido-3-phenylbenzo[e]pyrazolo[4,3-c][1,2]thiazin-4(1H)-yl)acetohydrazides.

A novel series of N'-(1-(aryl)ethylidene)-2-(5,5-dioxido-3-phenylbenzo[e]pyrazolo[4,3-c][1,2]thiazin-4(1H)-yl)acetohydrazides was synthesized. The synthesis was carried out by thermal method as well as ultrasonic bath to reduce reaction time and to enhance product yields. The synthesized compounds were characterized by spectroscopic techniques like NMR, infrared and EIMS. The structure of compound 5w was elucidated by X-ray crystallography. The titled compounds were evaluated for anti-human immunodeficiency virus type 1 (anti-HIV-1) and cytotoxic activities. Biological studies indicated that amongst these compounds, 5a, b, j, h and i showed the activity with median effective concentration (EC50) values less than 20 µM. Compound 5i exhibited the most potent anti-HIV-1 activity (EC50 = 3.2 µM) while 5h showed anti-HIV-1 activity (EC50 = 3.8 µM) with no toxicity at all in primary human lymphocytes, CEM and VERO cells.

Activation of water, ammonia, and other small molecules by PC(carbene)P nickel pincer complexes.

Nickel complexes of a PC(carbene)P pincer ligand framework are described. Dehydrobromination of the precursor (PC(sp)(3)P)NiBr in the presence of a donor (PPh3 or NC(t)Bu) leads to the title complexes, which feature a rare nickel-carbene linkage as the pincer ligand anchor point. This strongly donating, nucleophilic carbene center engages in a variety of E-H bond activations (E = H, C, N, O), some of which are reversible. This represents a new mode of bond activation by ligand cooperativity in nickel pincer complexes.

Reversible insertion of carbon dioxide into Pt(II)-hydroxo bonds.

The reactivity of three monomeric diimine Pt(II) hydroxo complexes, (NN)Pt(OH)R (NN = bulky diimine ligand; R = OH, ; R = C6H5, ; R = CH3, ) towards carbon dioxide has been investigated. Insertion into the Pt-OH bonds was found to be facile and reversible at low temperature for all compounds; the reaction with bis-hydroxide gives an isolable κ(2)-carbonato compound , with elimination of water.

Synthesis, characterization, and electrochemical studies of PPh(3-n)(dipp)(n) (dipp = 2,6-diisopropylphenyl): steric and electronic effects on the chemical and electrochemical oxidation of a homologous series of triarylphosphines and the reactivities of the corresponding phosphoniumyl radical cations.

Activation barriers to the electrochemical oxidation for the series PPh3-n(dipp)n (dipp = 2,6-diisopropylphenyl) in CH2Cl2/Bu4NPF6 were measured using large amplitude FT ac voltammetry. Increasing substitution across this series, which offers the widest range of steric requirements across any analogous series of triarylphosphines reported to date, increases the energetic barrier to electron transfer; values of 18, 24, and 25 kJ mol(-1) were found for compounds with n = 1, 2, and 3, respectively. These values are significantly greater than those calculated for outer sphere activation barriers, with deviations between observed and calculated values increasing with the number of dipp ligands. This suggests that the steric congestion afforded by these bulky substituents imposes significant reorganizational energy on the electron transfer processes. This is the first investigation of the effect of sterics on the kinetics of heterogeneous electron transfer across a structurally homologous series. Increased alkyl substitution across the series also increases the chemical reversibility of the oxidations and decreases the oxidation peak potentials. As the compounds for which n = 1 and 2 are novel, the synthetic strategies employed in their preparation are described, along with their full spectroscopic, physical, and crystallographic characterization. Optimal synthesis when n = 1 is via a Grignard reagent, whereas when n = 2 an aryl copper reagent must be employed, as use of a Grignard results in reductive coupling. Chemical oxidation studies were performed to augment the electrochemical work; the O, S, and Se oxidation products for the parent triarylphosphines for which n = 1 and 2 were isolated and characterized.

BN-Dibenzo[a,o]picenes: analogues of an unknown polycyclic aromatic hydrocarbon.

Reflecting on synthetic pinnacles: Whereas the parent hydrocarbon is not readily accessible, several examples of BN substituted-dibenzo[a,o]picenes can be prepared in two steps from known starting materials. These non-linear heptacene analogues are water-stable materials. Their preparation utilizes a potentially general method for preparing extended BN analogues of difficult-to-synthesize polycyclic aromatic hydrocarbon frameworks.

Silver(I) complex formation with cysteine, penicillamine, and glutathione.

The complex formation between silver(I) and cysteine (H2Cys), penicillamine (H2Pen), and glutathione (H3Glu) in alkaline aqueous solution was examined using extended X-ray absorption fine structure (EXAFS) and (109)Ag NMR spectroscopic techniques. The complexes formed in 0.1 mol dm(-3) Ag(I) solutions with cysteine and penicillamine were investigated for ligand/Ag(I) (L/Ag) mole ratios increasing from 2.0 to 10.0. For the series of cysteine solutions (pH 10-11) a mean Ag-S bond distance of 2.45 ± 0.02 Å consistently emerged, while for penicillamine (pH 9) the average Ag-S bond distance gradually increased from 2.40 to 2.44 ± 0.02 Å. EXAFS and (109)Ag NMR spectra of a concentrated Ag(I)-cysteine solution (C(Ag(I)) = 0.8 mol dm(-3), L/Ag = 2.2) showed a mean Ag-S bond distance of 2.47 ± 0.02 Å and δ((109)Ag) 1103 ppm, consistent with prevailing, partially oligomeric AgS3 coordinated species, while for penicillamine (C(Ag(I)) = 0.5 mol dm(-3), L/Ag = 2.0) the mean Ag-S bond distance of 2.40 ± 0.02 Å and δ((109)Ag) 922 ppm indicate that mononuclear AgS2 coordinated complexes dominate. For Ag(I)-glutathione solutions (C(Ag(I)) = 0.01 mol dm(-3), pH ∼11), mononuclear AgS2 coordinated species with a mean Ag-S bond distance of 2.36 ± 0.02 Å dominate for L/Ag mole ratios from 2.0 to 10.0. The crystal structure of the silver(I)-cysteine compound (NH4)Ag2(HCys)(Cys)·H2O (1) precipitating at pH ∼10 was solved and showed a layer structure with both AgS3 and AgS3N coordination to the cysteinate ligands. A redetermination of the crystal structure of Ag(HPen)·H2O (2) confirmed the proposed digonal AgS2 coordination environment to bridging thiolate sulfur atoms in polymeric intertwining chains forming a double helix. A survey of Ag-S bond distances for crystalline Ag(I) complexes with S-donor ligands in different AgS2, AgS2(O/N), and AgS3 coordination environments was used, together with a survey of (109)Ag NMR chemical shifts, to assist assignments of the Ag(I) coordination in solution.

1,4,6,9-Tetra-tert-butyl-2,7-dioxa-tricyclo-[6.3.0.0(3,6)]deca-3,8-diene.

The title compound, C(24)H(40)O(2), lies on an inversion center with a half-mol-ecule in the asymmetric unit. The central dioxane ring adopts a chair conformation. The four-membered ring is slightly puckered with a butterfly angle of 13.50 (14)°.

Ethyl 2-(3,4-dimethyl-5,5-dioxo-1H,4H-benzo[e]pyrazolo-[4,3-c][1,2]thia-zin-1-yl)acetate.

In the title mol-ecule, C(15)H(17)N(3)O(4)S, the heterocyclic thia-zine ring adopts a twist-boat conformation, which differs from that in related compounds, with adjacent S and C atoms displaced by 0.981 (4) and 0.413 (5) Å, respectively, on the same side of the mean plane formed by the remaining ring atoms. The mean plane of the benzene ring makes a dihedral angle of 23.43 (14)° with the mean plane of the pyrazole ring. In the crystal, mol-ecules are connected by weak C-H⋯O hydrogen bonds to form a three-dimensional network. The H atoms of the methyl group attached to the pyrazole ring were refined over six sites with equal occupancies.

4-Methyl-3-phenyl-2,4-dihydro-pyrazolo-[4,3-c][1,2]benzothia-zine 5,5-dioxide.

In the title mol-ecule, C(16)H(13)N(3)O(2)S, the heterocyclic thia-zine ring adopts a twist chair conformation with the S atom and an adjacent C atom displaced by 0.946 (5) and 0.405 (6) Å, respectively, on the same side of the mean plane formed by the remaining ring atoms. The mean planes of the benzene rings make dihedral angles of 16.61 (10) and 15.32 (10)° with the mean plane of the pyrazole ring. The mol-ecular structure is consolidated by intra-molecular C-H⋯N inter-actions and the crystal packing is stabilized by N-H⋯O and C-H⋯N hydrogen bonds. The crystal studied was an inversion twin with the refined ratio of the twin components being 0.53 (11):0.47 (11).

Propan-2-yl 2-(1,1,3-trioxo-2,3-dihydro-1λ(6),2-benzothia-zol-2-yl)acetate.

In the title mol-ecule, C(12)H(13)NO(5)S, the benzisothia-zole ring system is essentially planar (r.m.s. deviation = 0.0169 Å) as is the -C-C(=O)-O-C- sequence of atoms in the vicinity of the acetate group (r.m.s. deviation = 0.0044 Å). The mean plane of these atoms forms a dihedral angle of 88.41 (7)° with the benzisothia-zole ring system. In the crystal, weak C-H⋯O hydrogen bonds involving methyl-ene and methyne H atoms form R(4) (3)(20) graph-set motifs.

2-[2-(2-Chloro-phen-yl)-2-oxoeth-yl]-2,3-dihydro-1λ(6),2-benzothia-zole-1,1,3-trione.

The asymmetric unit of the title compound, C(15)H(10)ClNO(4)S, contains two independent conformers wherein the 2-chloro-phenyl group in one is rotated by approximately 180° compared to the other mol-ecule. This affects the S-N-C-C(=O) and N-C-C(=O)-C torsion angles giving vlaues of -87.0 (2) and 158.7 (2)° in one mol-ecule and -104.3 (2) and -173.4 (2)° in the other. The benzisothia-zole ring systems in the two mol-ecules are essentially planar (r.m.s. deviations = 0.017 and 0.010 Å) and form dihedral angles of 73.53 (7) and 73.26 (6)° with the benzene rings. In the crystal, there are weak π-π inter-actions between the benzene rings of the benzisothia-zole groups and symmetry-related chloro-benzene rings with centroid-centroid distances of 3.6178 (13) and 3.6267 (15) Å. In addition, pairs of weak inter-molecular C-H⋯O hydrogen bonds form inversion dimers which are connected by further C-H⋯O hydrogen bonds into a three-dimensional network.

2-(3,4-Dimethyl-5,5-dioxo-2H,4H-pyrazolo-[4,3-c][1,2]benzothia-zin-2-yl)-N-(2-fluoro-benz-yl)acetamide.

In the title mol-ecule, C(20)H(19)FN(4)O(3)S, the heterocyclic thia-zine ring adopts a half-chair conformation with the S atom displaced by 0.668 (4) Šfrom the mean plane formed by the remaining ring atoms. The mean planes of the benzene and pyrazole rings are inclined with respect to each other at a dihedral angle of 17.4 (3)°. The acetamide chain (O/N/C/C/C) linking the pyrazole and 2-fluoro-benzyl rings is essentially planar (r.m.s. deviation = 0.030 Å) and forms dihedral angles with the mean planes of these rings of 78.8 (2) and 78.89 (14)°, respectively. The crystal structure is stabilized by N-H⋯O and C-H⋯O hydrogen-bonding inter-actions, resulting in a six-membered ring with an R(2) (1)(6) motif, while C-H⋯O and C-H⋯F hydrogen-bonding inter-actions result in chains of mol-ecules lying along the c axis in a zigzag fashion.