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A selective oxidative Heck cross-coupling method was developed and optimized as a pivotal step for a synthetic route leading to the trans-stilbene framework. The developed method and synthesis were needed in a SAR study in progress that concerned design and development of an inhibitor for the human cell xCT antiporter system. The developed oxidative Heck cross-coupling method was examined with a variety of substrates and reagents to produce a library of different substituted trans-stilbenes, which revealed the method to hold a very good tolerance for an assortment of functional groups. The final synthetic route was successfully scaled-up (from mg scale) and performed in a 150 g (>1000×up-scaled) batch run to obtain an overall yield of 73 % (over three steps), which corresponds to a mean step yield of 90 %. The inhibitor candidate DC10 [(E)-5-(2-([1,1′-biphenyl]-4-yl)vinyl)-2-hydroxy-benzoic acid] was produced in multi-gram quantities (≈33 g) that subsequently was forwarded for animal efficacy and toxicology studies. The scaled-up process constitutes the first example of an oxidative Heck cross-coupling on >100-gram scale. publishedVersion

The xCT antiporter is a cell membrane protein involved in active counter‐transportation of glutamate (outflux) with cystine (influx) over the human cell membrane. This feature makes the xCT antiporter a crucial element of the biosynthesis of the vital free radical scavenger glutathione. The prodrug sulfasalazine, a medication for the treatment of ulcerative colitis, was previously proven to inhibit the xCT antiporter. Starting from sulfasalazine, a molecular scaffold jumping followed by SAR‐assisted design and synthesis provided a series of styryl hydroxy‐benzoic acid analogues that were biologically tested in vitro for their ability to decrease intracellular glutathione levels using four different cancer cell lines: A172 (glioma), A375 (melanoma), U87 (glioma) and MCF7 (breast carcinoma). Depletion of glutathione levels varied among the compounds as well as among the cell lines. Flow cytometry using propidium iodide and the annexin V marker demonstrated minimal toxicity in normal human astrocytes for a promising candidate molecule (E)‐5‐(2‐([1,1′‐biphenyl]‐4‐yl)vinyl)‐2‐hydroxybenzoic acid., Glutathione is one of the cells major protective means against oxidative stress. The biosynthesis of glutathione use cystine as substrate that is transported into the cell by the xCT antiporter. Sulfasalazine was known to be an xCT antiporter inhibitor and was used as a lead compound. The team performed scaffold hopping, molecular moiety truncations, and bioisostere alteration to synthesize a library of novel xCT antiport inhibitor candidates that was evaluated in vitro for four various cell lines with various xCT expression.

A general and selective Pd-catalyzed cross-coupling of aromatic boronic acids with vinyl-imidazoles is disclosed. Unlike most cross-coupling reactions, this method operates well in absence of bases avoiding the formation of by-products. The reactivity is highly enhanced by the presence of nitrogen-based ligands, in particular bathocuproine. The method involves MnO2 as oxidant for the oxidation Pd (0)→Pd (II), a much weaker oxidant than previously reported in the literature. This allows for the use of reactants that possess a multitude of functional groups. A scope and limitation study involving a series of 24 boronic acids, whereof 18 afforded TMs in yields in the range 41–95%. The disclosed method constitutes the first general method for the oxidative Heck cross-coupling on the imidazole scaffold, which moreover operates with a selection of other heterocycles. publishedVersion

A previously designed and developed 12-step total synthesis that includes [1,1'-biphenyl]-2-amine and carbazole intermediates and that ultimately produces the carbazole alkaloid carbazomycin G was exploited as a screening compound library with the goal of identifying potential lead compound(s) with cytotoxic effect. These compounds were investigated by using in-vitro tests involving the two human cell lines HL-60 and MOLM-13, which both model acute myeloid leukaemia (AML). The in-vitro biological test results were used together with the molecular structures of the various intermediates in a concise SAR analysis. Several of the intermediates revealed cytotoxicity (IC50

A selective and high-rate Ru-catalyzed cross-metathesis reaction of alkenes with vinylimidazole is disclosed. Cross-metathesis is known to operate less efficiently on N-heterocycles, but through optimization by means of statistical experimental design and multiple regression, optimal reaction conditions were identified that allowed for consistent high-yields without the need of overly complicated set-ups or additives. The method was tested on a series of terminal alkene reagents with a variety of different functional groups and it provides the corresponding target molecules in good to high yields. publishedVersion

BACKGROUND Although withdrawn from the market due to cardiotoxicity, we showed that the antipsychotic drug Thioridazine shows chemosensitizing effects in combination with Temozolomide (TMZ) for the treatment of glioblastoma multiforme (GBM). Based on our prior observations, the aim of this study was through medicinal chemistry, to design and synthesize new compounds based on Thioridazines tricyclic structure, and to determine their therapeutic potential. METHODS Fourteen compounds were synthesized where variations were made within the tricyclic side chains. The newly synthesized compounds were screened for therapeutic efficacy with or without TMZ using a WST-1 cell viability assay and real-time imaging system (IncuCyte). Tests were performed on both monolayer cell cultures, as well as on glioma stem cell spheroids (GSC). The therapeutic effects were also studied on human astrocytes (NHA) as well as on rat brain organoids (BO). Annexin V/propidium iodide (PI) double staining followed by flow cytometric analysis was performed after 48 hours of treatment. RESULTS Following an extensive screening, we identified two novel compounds (EA01 and EA02) that at concentrations of 4 and 9.5 µM showed a strong cytotoxicity on GBM cell lines (U-87 MG p< 0,0001, U251 p< 0,0001, LN18 p= 0,0004) as well as on glioma stem cells (GSC) (P3 p< 0,0001) compared to NHA and BOs respectively. Also, when BOs were confronted with GSC spheres in an invasion assay, a selective cytotoxicity was observed in the GSCs. Mechanistically, we show that both compounds induce apoptosis in GBM cells. Moreover, intravenous delivery of increasing concentrations of EA01 and EA02 revealed no toxicity in animals at concentrations up to 21 mg/kg. CONCLUSION We developed two new tricyclic therapeutic compounds that show a strong selective cytotoxicity in GBM cells with limited systemic toxicity in animals. Ongoing studies are investigating the therapeutic potential of EA01 and EA02 in orthotopic xenografts in vivo.

Primary and benzylic alcohols were cost-effectively transformed into their corresponding nitriles using a classical batch approach and a continuous flow process implemented on a multi-jet oscillating disk (MJOD) reactor platform. The alcohols as substrates were treated with a (2,2,6,6-tetra-methylpiperidin-1-yl)oxidanyl (TEMPO) free radical as the pre-catalyst with 1,3-dichloro-5,5-dimethylhydantoin (DCH) as the terminal oxidant to produce their corresponding carbonyl compounds. The reaction was conducted at a reaction temperature of 35 °C and a flow reactor residence time of 5 min. This alcohol to carbonyl oxidation step was telescoped with a subsequent step that involved treatment with aqueous ammonium hydroxide and 1,3-diiodo-5,5-dimethylhydantoin (DIH) at a reaction temperature of 65 °C with concomitant oxidation to nitrile using a flow reactor residence time of 15 min. A solvent exchange process was conducted in-between the two synthetic reaction steps by means of an in-line extraction process with ethyl acetate, a step that was concatenated by using an in-line liquid–liquid separation process using a hold-up tank. The second synthetic step was revealed to be tuneable, since four distinct products might be produced at varying degrees of selectivity. When DIH was used as the terminal oxidant, a high selectivity towards the original target nitrile was achieved, but if DIH was replaced with DCH as the terminal oxidant, 1,2-di((E)-benzylidene)hydrazine and two different stereoisomers of the 1,3,5-triazabicyclo[3.1.0]hexane scaffold were produced. The selectivity towards the various products was highly influenced by the reaction temperature. A scope and limitation study of the nitrile process with an assortment of primary alcohols as substrates provided excellent yields which revealed good functional group tolerance.

Metastatic tumors with moderate radiosensitivity account for most cancer-related deaths, highlighting the limitations of current radiotherapy regimens. The xCT-inhibitor sulfasalazine (SAS) sensitizes cancer cells by blocking xCT-mediated cystine uptake, and thereby glutathione (GSH) synthesis protecting against radiation-induced oxidative stress. However, SAS has limited clinical potential as a radiosensitizer due to side effects and low bio-availability. Using SAS as a starting point, we previously developed synthetic xCT-inhibitors through scaffold hopping & structure optimization aided by structure-activity relationship analysis (SAR). Notably, the compound DC10 exhibited potent inhibition of GSH synthesis. In this study, we validated DC10 as a radiosensitizer in the xCT-expressing cancer cell lines A172, A375 & MCF7 in vitro & in mice harboring melanoma xenografts. After DC10 treatment, we measured 14C-cystine uptake in the cancer cell lines using liquid scintillation counting, and intracellular levels of GSH & reactive oxygen species (ROS) using luminescence assays. We performed immunoblotting for γH2AX & ATM to assess DNA damage after treatment with DC10 and radiotherapy. We then assessed the effect of adding DC10 to radiation upon cancer cell colony formation. Blood samples from mice treated with DC10 underwent biochemical analysis to assess toxicity. Finally, mice with A375 melanomas in the flank, received DC10 and radiotherapy in combination, as monotherapies or no treatment. Notably, DC10 reduced cystine uptake and GSH synthesis & increased ROS levels in a dose-dependent manner. Furthermore, DC10 interacted synergistically with radiation to increase DNA damage & reduce colony formation. Mice receiving DC10 were clinically unaffected, whereas blood samples analyses to assess bone marrow suppression, liver or kidney toxicity revealed no significant differences between mice & untreated controls. Importantly, DC10 potentiated the anti-tumor efficacy of radiation in mice with melanoma xenografts. We conclude that DC10 acts as a radiosensitizer, is well tolerated, & mediates its effect by inhibiting cystine uptake, leading to GSH depletion and increased oxidative stress. Thus, our findings demonstrate the feasibility of using synthetic xCT-inhibitors to overcome radioresistance. The expression of xCT in multiple tumor types further implies it represents a target generic to cancer rather than confined to tumor subtypes. Hence, this therapeutic concept could be applicable to a wide range of radioresistant malignancies. Citation Format: Shahin Sarowar, Davide Cirillo, Pablo Jativa, Mette H. Nilsen, Sarah-Muheha A. Otragane, Jan I. Heggdal, Frode Selheim, Valentín Ceña, Hans-René Bjørsvik, Per Øyvind Enger. Styrylbenzoic acid derivative DC10 potentiates radiotherapy by inhibiting glutathione synthesis, leading to increased oxidative stress and cancer cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 214.

A series of N-aryl- and N-alkyl substituted imidazoles has been synthesised and complexed with Ag+ to obtain silver-NHC complexes of the form [Ag(NHC)2 ]X. These silver-NHC complexes were tested in vitro against the human cell lines HL-60 and MOLM-13, which both model acute myeloid leukaemia (AML). A substantial difference in cytotoxicity was revealed varying in the range 13-4 μM and 22-9 μM for HL-60 and MOLM-13, respectively. Furthermore, this study revealed that when an alkyl group is installed on the imidazole scaffold, its position substantially influences the cytotoxicity of the corresponding silver NHC complex.

A three step continuous/semi-flow process leading to the fungicide Boscalid® is disclosed. The first step of the process is a Suzuki cross-coupling where 1-chloro-2-nitrobenzene is coupled with 4-chlorophenylboronic acid at a temperature of 80 °C using a solvent mixture of ethanol/water as the reaction medium with sodium carbonate as the base and tetrakis(triphenylphosphine)-palladium as the catalyst. This reaction step was developed as a batch procedure and then adapted and implemented on a multi-jet oscillating disk (MJOD) continuous flow reactor platform. The intermediate 4′-chloro-2-nitro-1,1′-biphenyl was achieved in high yield (82%). The second step which was telescoped with the first one involved a nitro group reduction of high efficacy. The reduction method was based on NaBH4/CoSO4·7H2O as the reduction system. The reduction product 2-amino-4′-chloro-1,1′-biphenyl was achieved in high yield (79%) at a short reactor residence time (3 min). The final step of the process is composed of a two-step sequence where 2-amino-4′-chloro-1,1′-biphenyl is transformed into the corresponding iminosulfanone intermediate (not isolated), which immediately reacts with the 2-chloronicotinic acid present in the reaction mixture to form Boscalid® in a yield of >66%. The three-step process provided an overall yield of >42%, which corresponds to a mean step yield of ≈75%.

BACKGROUND Although withdrawn from the market due to cardiotoxicity, we have shown that the antipsychotic drug Thioridazine shows chemosensitizing effects in combination with Temozolomide (TMZ) for the treatment of glioblastoma multiforme (GBM). Based on our prior observations, the aim of the presented project was through medicinal chemistry, to design and synthesize new compounds based on Thioridazines tricyclic structure, and to determine their therapeutic potential. MATERIAL AND METHODS Fourteen compounds were synthesized where variations were made within the tricyclic side chains. The newly synthesized compounds were screened for therapeutic efficacy with or without TMZ using a WST-1 cell viability assay as well as a real-time imaging system (IncuCyte). Tests were performed on both monolayer cell cultures, as well as on glioma stem cell spheroids (GSC). The therapeutic effects were also studied on human astrocytes (NHA) as well as on rat brain organoids (BO). Annexin V/propidium iodide (PI) double staining followed by flow cytometric analysis was performed after 48 hours of treatment. RESULTS Following an extensive screening, we identified two novel compounds (EA01 and EA02) that at concentrations of 4 and 9.5 µM showed a strong cytotoxicity on GBM cell lines (U-87 MG p CONCLUSION We have developed two new tricyclic therapeutic compounds that show a strong selective cytotoxicity in GBM cells with limited systemic toxicity in animals. Ongoing studies are investigating the therapeutic potential of EA01 and EA02 in orthotopic xenografts in vivo.

An efficient method for the synthesis of the carbazole scaffold was designed and investigated. The method was developed to produce substituted carbazoles by an intramolecular combination of a free amine group and an arene. The steps of the method involved tandem Pd-catalyzed C–H activation and intramolecular C–N bond formation. The method showed good functional group tolerance, and substituent(s) could be on either of the two rings or on both of the two rings of the 2-aminobiphenyl substrate. After ring closure, the reduced Pd catalyst was oxidized to PdII by hydrogen peroxide. The novel method was also demonstrated to operate excellently with the corresponding 2-N-acetylaminobiphenyls.

A simple and efficient method for Suzuki cross-coupling of highly substituted and congested 1-chloro-2-nitrobenzene with phenylboronic acid was developed, investigated, and optimized. The reaction conditions comprises a mixture of MeOH and water (4:1) as the reaction medium, readily available and cheap Pd(PPh3)4 as catalyst, sodium carbonate as base, and microwave heating, which affords a fast reaction rate with good outcomes. The procedure was proven to have high functional group tolerance with phenylboronic acid and for 1-chloro-2-nitrobenzene and thus is a general method for the synthesis of 2-nitrobiphenyl. The target scaffold, 2-nitrobiphenyls, was produced in excellent yields with excellent selectivities in all cases.

A batch synthesis to the iodinating agent 1,3-diiodo-5,5-dimethyl-imidazolidine-2,4-dione (DIH) was devised and developed. This batch process was then up-scaled (10×) and optimized by means of statistical experimental design and multivariate regression. The optimized batch procedure was then transferred and adapted for continuous flow synthesis using a multi-jet oscillating disk (MJOD) continuous flow reactor platform to provide a flow process that allowed a throughput of 47 g h−1 with a residence time of 9 min. A semi-continuous work-up step based on vacuum filtration was established and successfully telescoped to be an integrated part of the flow process. An 8 h test run using the optimized flow synthesis in combination with the semi-continuous filtration step afforded 375 g (≈90% isolated yield) of the pure title compound that was collected from 14 filtration batches of 25–27 g each.

Computational chemistry has shown that backbone-alkylated imidazoles ought to be efficient ligands for transition metal catalysts with improved carbene-to-metal donation. In this work, such alkylated imidazoles were synthesized and complexed with silver(I) by means of an eight/nine-step synthetic pathway we devised to access a new class of biologically active silver complexes. The synthesis involves selective iodination of the imidazole backbone, followed by Sonogashira coupling to replace the backbone iodine. The installed alkyne moiety is then subjected to reductive hydrogenation with Pearlman’s catalyst. The imidazole N1 atom is arylated by the palladium-catalyzed Buchwald N-arylation method. The imidazole N3 position was then methylated with methyl iodine, whereupon the synthesis was terminated by complexation of the imidazolium salt with silver(I) oxide. The synthetic pathway provided an overall yield of ≈20 %. The resulting complexes were tested in vitro against HL60 and MOLM-13 leukemic cells, two human-derived cell lines that model acute myeloid leukemia. The most active compounds exhibiting low IC50 values of 14 and 27 μM, against HL60 and MOLM-13 cells, respectively. The imidazole side chain was found to be essential for high cytotoxicity, as the imidazole complex bearing a C7 side chain at the 4-position was four- to sixfold more potent than the corresponding imidazole elaborated with a methyl group. publishedVersion

A Sonogashira coupling reaction method to join terminal alkynes to the imidazole backbone was developed and investigated. The method exhibits good functional group tolerance and provides target 4-alkynylated imidazoles in 70–93 % yield. The alkyne reagents were characterized by means of DFT calculations, from which electrostatic potential surfaces (EPS) were produced. A clear correlation between the EPS of the triple bond and the success of the coupling reaction was revealed. If the EPS is in range –94 to –105 kJ mol–1 the coupling is successful. An unsuccessful class of reagents (alkynols) was made compatible by means of an auxiliary group (tert-butyldimethylsilyl). EPSs of these modified reagents then resembled those of the model and these auxiliary-assisted reagents then coupled successfully in excellent yields.

Peroxy acids can be used as the terminal oxidant for the Baeyer–Villiger oxidation of acetophenones and for direct ring hydroxylation of methoxy-substituted benzenes. An oxidative system involving 3-chloroperbenzoic acid (mCPBA) and 2,6-dimethoxyacetophenone as model substrate was investigated by means of statistical experimental design, multivariate modelling and response surface methodology. The outcome of the organic peracid oxidation experiments was portrayed by a multi-response matrix consisting of the yields of three different compounds; 2,6-dimethoxyphenyl acetate, 1-(4-hydroxy-2,6-dimethoxy-phenyl)ethanone and 3-hydroxy-2,6-dimethoxy-phenyl acetate. The optimized reaction protocol was utilized to investigate a series of various substituted acetophenones. The overall investigation revealed that both the molecular structure of the acetophenone substrate and the experimental conditions exhibited a substantial impact on whether the oxidation reaction follows the oxygen insertion or direct ring hydroxylation mechanism. An improved protocol for the direct ring hydroxylation was also obtained from the experimental and modelling described herein. Copyright © 2015 John Wiley & Sons, Ltd.

We have revisited the Stille coupling reaction for the functionalization of the imidazole backbone. In this context CuI was exploited as a co-catalyst, which resulted in significantly improved yields of target coupling products. Furthermore, a systematic investigation of the effect of the auxiliary group on the N-1-ring atom was performed. When mono-coupling is desired, the Tosyl (Tos) group is superior to the (dimethylamino)sulfonyl (DMAS) group, furnishing the corresponding 4-coupled imidazoles in significantly higher yields. However, when bis-coupling is preferred, the DMAS group is imperative for success of the coupling procedure. Utilizing this reaction protocol, we were successfully able to demonstrate the first examples of Stille bis-coupling utilizing N-DMAS-4,5-diiodoimidazole as substrate.

An improved and simplified In-based protocol for the reduction of 2-nitro-1,1′-biphenyls to the corresponding 2-amino-1,1′-biphenyls is disclosed. The method utilizes only a stoichiometric quantity of indium powder as the reducing reagent along with a stoichiometric quantity of ammonium chloride. The work-up is very simple, it requires only a simple filtration of the post-reaction mixture whereupon the reaction medium is removed under reduced pressure. The method was also proven to operate with a variety of functional groups to provide high to excellent yields of the target 2-amino-1,1′-biphenyls. A proposal for a reaction mechanism is also provided.

The multijet oscillating disk (MJOD) flow reactor is a relatively new technology for continuous flow synthesis. This technology is still under investigation as an all-round platform for flow synthesis. In this article, findings are disclosed from a project where a MJOD flow reactor rig (reactor volume of ≈50 mL) was investigated as the reaction platform for ring closing metathesis and cross (self) metathesis reaction, using reaction mixture volumes down to only ≈5 mL. The Hoveyda–Grubbs second-generation catalyst was used without an inert atmosphere. The results of the flow synthesis provided excellent selectivity and high yield. For comparison purposes, the syntheses conducted in the MJOD reactor were compared with similar literature experiments performed with other flow technologies and batch conditions.

3,3,4,4-Tetraethoxybut-1-yne (TEB) is a versatile synthon that can be produced in a four-step synthesis. The third step of the synthesis is a cycloproanation, which has been thoroughly investigated and optimized by means of statistical experimental design and multivariate modeling. At the outset, an exhaustively pre-experimental design was performed resulting in a copious Ishikawa cause–effect diagram. In total six of the experimental variables were assessed to be of large importance and thus selected for further investigation by fractional factorial design. The results of that screening and first step optimization formed the basis for a response surface modeling (RSM) study. The RSM investigation was completed by using a central composite design from which a response surface was graphically produced as an iso-contour projection. The derived multivariate predictive model in terms the iso-contour projection plots were ultimately utilized to establish experimental conditions that concomitantly provided exce...

The development of a multivariate study for a quantitative analysis of six different polybrominated diphenyl ethers (PBDEs) in tissue of Atlantic Salmo salar L. is reported. An extraction, isolation, and purification process based on an accelerated solvent extraction system was designed, investigated, and optimized by means of statistical experimental design and multivariate data analysis and regression. An accompanying gas chromatography-mass spectrometry analytical method was developed for the identification and quantification of the analytes, BDE 28, BDE 47, BDE 99, BDE 100, BDE 153, and BDE 154. These PBDEs have been used in commercial blends that were used as flame-retardants for a variety of materials, including electronic devices, synthetic polymers and textiles. The present study revealed that an extracting solvent mixture composed of hexane and CH₂Cl₂ (10:90) provided excellent recoveries of all of the six PBDEs studied herein. A somewhat lower polarity in the extracting solvent, hexane and CH₂Cl₂ (40:60) decreased the analyte %-recoveries, which still remain acceptable and satisfactory. The study demonstrates the necessity to perform an intimately investigation of the extraction and purification process in order to achieve quantitative isolation of the analytes from the specific matrix.

A multijet oscillating disk (MJOD) millireactor system suitable for operating at cryogenic temperatures has been developed, assembled, and investigated. This new reactor system (cryoMJOD) was realized with the purpose to prepare various phenylboronic acids in a continuous two (three)-step telescoped synthetic process at temperatures in the interval −50 to −75 °C. In this process, n-butyllithium was reacted with a phenylbromide to provide the corresponding phenyllithium derivative, whereupon a borate was added under the formation of target product phenylboronic acid in good selectivity and medium-to-good yield (50–75%). These results were competitive with results previously revealed in the literature. The residence times of the telescoped two-step process were considerably shorter compared to those of batch mode operations for the identical syntheses. The flow process was optimized by means of statistical experimental design and multivariate regression, upon which the process was utilized for the productio...

Organic solvent nanofiltration (OSN) is a recently commercialized technology, which we have used to develop a method for the separation of a target product and the Pd catalyst from a Heck coupling postreaction mixture. The experimental setup included commercially available polyimide copolymer membranes with molecular weight cut-off (MWCO) values in the range of 150-300 Da, acetone as the solvent, and a working pressure (N(2)) of 3 MPa. The investigation of the membranes revealed that a membrane with a MWCO of 200 Da provided quantitative retention of the Pd catalyst and quantitative recovery of the target product by means of a cross-flow dia-nanofiltration procedure.

This report discloses proof of concept and experimental results from a project involving design, development, and investigation of a novel approach for flow chemistry and the realization of equipment operating according to this new approach. This device is named multijet oscillating disk (MJOD) reactor and is dedicated to continuous flow organic synthesis in milliscale. Characteristics such as the importance of the multijet disk unit, with or without oscillating, and possible limitations, such as back-mixing, have been explored, and the flow system is benchmarked with other technologies. Several well-known reactions and syntheses usefully both in the chemical industry as well as in the research laboratory have been conducted using the new system, which have been benchmarked with batch- and microreactor protocols. In particular the Haloform reaction, the Nef reaction, nucleophilic aromatic substitution, the Paal–Knorr pyrrole synthesis, sodium borohydride reduction, O-allylation, the Suzuki cross-coupling ...

An environmentally benign, convenient, high yielding, and cost-effective synthesis leading to idebenone is disclosed. The synthesis includes a bromination process for the preparation of 2-bromo-3,4,5-trimethoxy-1-methylbenzene, a protocol for the Heck cross-coupling reaction using either thermal or microwave heating, olefin reduction by palladium catalyzed hydrogenation, and a green oxidation protocol with hydrogen peroxide as oxidant to achieve the benzoquinone framework. The total synthesis is composed of six steps that provide an overall yield of 20% that corresponds to a step yield of 76%.

An efficient high-yielding and environmentally benign switchable oxidation process that can selectively produce two different versatile synthetic intermediates is disclosed. One of the two intermed...

A multivariate design and optimization study for the synthesis of the bromoalkanol 10-bromo-1-decanol using decane-1,10-diol as substrate is reported. The bromination process was supported by the phase transfer catalyst tetrabutylammonium bromide with aqueous HBr (48%) as the brominating reagent. The optimized batch protocol provided a yield of 64% of 10-bromo-1-decanol 2 TM with a conversion of 80%, and 10% of the dibrominated alkane 1,10-dibromodecane 3, a characteristic byproduct, was formed.

A new sterically demanding bidentate imidazolium bromide has been prepared and used as ligand precursor for the synthesis of the corresponding NHC–silver(I) complex. The X-ray analysis of the silver(I) complex revealed a rare Ag4O4 core cubane cluster. The silver(I) complex reacts readily with the Grubbs first generation catalyst providing a labile alkylidene complex. When the transmetallation was attempted with Hoveyda–Grubbs first generation catalyst in the presence of THF as solvent, two very stable phosphine free bis-bidentate N-heterocyclic carbene complexes, one green and one orange, were formed. Notably, one of these complexes is the first observation of a metal alkylidene group substituted by a NHC ligand, a surprising result since the new complex is formally derived from a nucleophile substitution of a hydride by a NHC ligand on the alkylidene carbon. A proposal for the reaction mechanism is elaborated.

A density functional theory-based computational comparison of various [Ru]−L bonds in L(PCy3)Cl2RuCH2 complexes, where L is a dative ligand, shows that similar bond strengths can be expected for ru...

A simple, green synthetic protocol to bidentate Schiff base substituted ruthenium carbene complexes is described. These complexes are potent catalysts for olefin metathesis, but the original synthetic route employs the Schiff base ligands in the form of highly toxic thallium(I) salts. The new protocol involves a two-step, quasi-one-pot approach and silver(I) carbonate as base. The target ruthenium carbene complexes are obtained in yields that are similar to, or better than, those of the original protocol.

A telescoped process for the preparation of 2-methoxy-3-methyl-[1,4]benzoquinone is disclosed. When this novel process is compared to the prevailing method that utilizes Na2Cr2O7 as the oxidant, the novel process represents a high yielding (95%), green, and environmentally benign alternative with H2O2 and HNO3 as the oxidants and CH3COOH as the reaction medium.

A new catalytic oxidation method for the preparation of aromatic carboxylic acids from methyl aryl ketones is reported. The method is an alternative to the haloform reaction; it is benign and affords the desired product without production of any harmful side products. The catalytic cycle is based on the use of an electron-deficient nitroarene as catalyst with either of the two cheap and green oxidants sodium percarbonate or sodium perborate. The method gives a good yield (87%) and shows excellent selectivity when the model substrate (acetophenone) is oxidized. A series of benzoic acids of industrial interest were prepared by means of this method.

Multivariate modeling and spectroscopy taken together constitute a powerful tool applicable to both process monitoring and to process and reaction optimizing. The present article establishes how near-IR spectroscopy utilizing a fiber-optical transmission probe can be combined with principal component analysis to extract concentration profiles from a set of spectra recorded during the course of a reaction. Moreover, it is demonstrated how to easily determine the end-point (optimized reaction time, that is, the minimized time) of a reaction, and a simple calibration for quantitative analysis is demonstrated.

This is a general overview of some first-, second- and third-generation fine chemicals with origins from the lignin oxidation process. The synthetic organic processes of these substances are presented as well as several applications for the synthesis of a variety of pharmaceutical chemicals.

Results from a process improvement project for preparation of 3-R-quinuclidinol, a highly valuable intermediate for several muscarine-active compounds are described. The studied process was based o...

This contribution presents results from a development and optimisation project concerning a synthetic process for iodixanol. Iodixanol is the “active ingredient” in Visipaque (Nycomed Amersham now Amersham Health) a medical X-ray imaging contrast agent. The process step that was developed and optimised comprised a reaction between a tetraacid chloride and 3-aminopropane-1,2-diol for obtaining the corresponding tetraamide. This reaction was originally performed using DMA as reaction medium, a reaction that gave a medium-to-high yield of the tetraamide. Solvent screening was performed followed by process optimisation using response surface methodology. Surprisingly, a solvent mixture composed by 1:2 v/v THF:water was determined to be a superb reaction medium. Tuning the experimental condition according to the developed multivariate empirical model gave an excellent yield of the target molecule, nearly 94% with only small quantities of the main side product, monoacid triamide, which indicates a rather low hy...

A number of secondary metabolites resembling a polysubstituted 2-aminoimidazole scaffold are found in a variety of marine sponges. Due to the diversity in the biological activity with drug-like properties, several research groups have designed and developed strategies and syntheses leading to these marine alkaloids. This report constitutes a summary of the literature during the period 1990 to the mid 2012 that presents syntheses belonging to seven different classes of marine alkaloids based on the imidazole scaffold, namely, preclathridines A–C, clathridines A–C, isonaamines A–E, isonaamidines A–E, naamines A–G, naamidines A–I, and pyronaamidines.

A new synthetic process for oxidation of methyl ketones into their corresponding carboxylic acids using a modified alkaline nitrobenzene method is described. By introduction of a more powerful oxidant, such as 1,3-dinitrobenzene, the oxidation reaction proceeds smoothly in aqueous alkaline solution at 100 °C. The procedure can also be used for oxidation of benzaldehydes and benzyl alcohols into carboxylic acids and to oxidise mandelic acid into its α-keto form, whereas prolonged reaction time results in decarboxylation and gives thus also in this case benzoic acid.

New synthetic procedures for vanillin, iso-vanillin, heliotropin, and protocatechualdehyde starting from catechol are described. The utilisation of statistical experimental design and multivariate modelling and the mechanistic interpretation of the acid and base catalysis in the condensation of catechol derivatives with glyoxylic acid and in the regiocontrolled methylation of protocatechualdehyde and of the Cu(II) salt catalysis in the oxidative decarboxylation of mandelic acid derivatives have allowed the development of new highly selective processes.