We report the discovery that simple carboxylic acids, such as benzoic acid, boost the activity of N‐heterocyclic carbene (NHC) catalysts in the oxidative esterification of aldehydes. A simple and ...efficient protocol for the transformation of a wide range of sterically hindered α‐ and β‐substituted aliphatic aldehydes/enals, catalyzed by a novel and readily accessible N‐Mes‐/N‐2,4,6‐trichlorophenyl 1,2,4‐triazolium salt, and benzoic acid as co‐catalyst, was developed. A whole series of α/β‐substituted aliphatic aldehydes/enals hitherto not amenable to NHC‐catalyzed esterification could be reacted at typical catalyst loadings of 0.02–1.0 mol %. For benzaldehyde, even 0.005 mol % of NHC catalyst proved sufficient: the lowest value ever achieved in NHC catalysis. Preliminary studies point to carboxylic acid‐induced acceleration of acyl transfer from azolium enolate intermediates as the mechanistic basis of the observed effect.
While N‐heterocyclic carbene (NHC) catalyzed oxidative esterification of aldehydes/enals is synthetically highly attractive, it is plagued by poor conversions/yields for sterically demanding substrates. The triazolium catalyst shown, with benzoic acid as co‐catalyst, overcomes this deficiency. A variety of hitherto recalcitrant aldehydes/enals are efficiently converted to esters with very low catalyst loadings (down to 50 ppm).
Under aprotic conditions, the stoichiometric reaction of N‐heterocyclic carbenes (NHCs) such as imidazolidin‐2‐ylidenes with aldehydes affords Breslow Intermediates (BIs), involving a formal ...1,2‐C‐to‐O proton shift. We herein report kinetic studies (NMR), complemented by DFT calculations, on the mechanism of this kinetically disfavored H‐translocation. Variable time normalization analysis (VTNA) revealed that the kinetic orders of the reactants vary for different NHC‐to‐aldehyde ratios, indicating different and ratio‐dependent mechanistic regimes. We propose that for high NHC‐to‐aldehyde ratios, the H‐shift takes place in the primary, zwitterionic NHC‐aldehyde adduct. With excess aldehyde, the zwitterion is in equilibrium with a hemiacetal, in which the H‐shift occurs. In both regimes, the critical H‐shift is auto‐catalyzed by the BI. Kinetic isotope effects observed for R‐CDO are in line with our proposal. Furthermore, we detected an H‐bonded complex of the BI with excess NHC (NMR).
Under aprotic conditions, Breslow intermediates can be generated from N‐heterocyclic carbenes such as imidazolidin‐2‐ylidenes and aldehydes. But how is the intermediary “primary adduct” (PA) converted to the diaminoenol (BI)? Our kinetic study shows that the highly unfavorable 1,2‐C‐to‐O H‐shift is autocatalyzed by the Breslow intermediate, and that a hemiacetal plays a crucial role in the presence of excess aldehyde.
Cancer treatment is greatly challenged by drug resistance, highlighting the need for novel drug discoveries. Here, we investigated novel organoarsenic compounds regarding their resistance-breaking ...and apoptosis-inducing properties in leukemia and lymphoma. Notably, the compound (2,6-dimethylphenyl)arsonic acid (As2) demonstrated significant inhibition of cell proliferation and induction of apoptosis in leukemia and lymphoma cells while sparing healthy leukocytes. As2 reached half of its maximum activity (AC50) against leukemia cells at around 6.3 µM. Further experiments showed that As2 overcomes multidrug resistance and sensitizes drug-resistant leukemia and lymphoma cell lines to treatments with the common cytostatic drugs vincristine, daunorubicin, and cytarabine at low micromolar concentrations. Mechanistic investigations of As2-mediated apoptosis involving FADD (FAS-associated death domain)-deficient or Smac (second mitochondria-derived activator of caspases)/DIABLO (direct IAP binding protein with low pI)-overexpressing cell lines, western blot analysis of caspase-9 cleavage, and measurements of mitochondrial membrane integrity identified the mitochondrial apoptosis pathway as the main mode of action. Downregulation of XIAP (x-linked inhibitor of apoptosis protein) and apoptosis induction independent of
(B-cell lymphoma 2) and caspase-3 expression levels suggest the activation of additional apoptosis-promoting mechanisms. Due to the selective apoptosis induction, the synergistic effects with common anti-cancer drugs, and the ability to overcome multidrug resistance in vitro, As2 represents a promising candidate for further preclinical investigations with respect to refractory malignancies.
Introduction
The active compound (E)‐1‐(3′,4′‐dimethoxyphenyl)butadiene (DMPBD) isolated from the rhizomes of Zingiber cassumunar Roxb. has potent anti‐inflammatory and anticancer activities. ...Although DMPBD is one of the promising drug candidates for phytomedicine, its limited stability impedes its widespread use. For the development of new drugs, the assessment of their chemical stability is essential, ensuring they maintain their properties within specified limits throughout the period from production until use.
Objective
In the present study, we aimed to evaluate the stability of DMPBD under various conditions, including different solvents, temperatures, and lighting conditions, to identify the factors affecting stability and optimize the storage and handling conditions.
Methodology
DMPBD samples subjected to the different conditions tested were monitored by quantitative 1H NMR (qHNMR), using an internal standard for the determination of the absolute quantity of DMPBD as a function of time and the changes thereof within 1 month.
Results
Significant decomposition of DMPBD was observed in chloroform‐d1, whereas its content remained constant in methanol‐d4. The content of DMPBD was maintained upon storage at temperatures below 4°C, both as methanolic solution and in the crude extract. Exposure to light had a slight negative impact on its contents. Some degradation products could be identified as resulting from O2‐induced cleavage of the diene moiety.
Conclusions
For pharmacological/therapeutic applications, DMPBD should be stored in the form of the crude extract or as a purified material in methanolic solution. Ideally, the storage temperature should be below 4°C and O2 should be excluded.
The stability of DMPBD under various conditions was studied using qHNMR to monitor its changes in content over 1 month. Solvent and storage temperature significantly influenced the stability of DMPBD, while light exposure had a slight negative impact on its stability. The DMPBD content remained constant upon storage at temperatures below 4°C, both as a methanolic solution and in the crude extract. Some degradation products could be identified as resulting from O2‐induced cleavage of the diene moiety.
The first generation and X‐ray diffraction (XRD) analysis of a crystalline Breslow intermediate (BI) derived from a thiazolin‐2‐ylidene, that is, the aromatic heterocycle present in vitamin B1, is ...reported. Key to success was the combined use of pentafluorobenzaldehyde and a thiazolin‐2‐ylidene carrying an enol‐stabilizing dispersion energy donor as N‐substituent. A so‐called primary intermediate (PI) could be isolated in protonated form (pPI) as well and analyzed by XRD. Furthermore, the first stable BI derived from an aromatic thiazolin‐2‐ylidene and an aliphatic aldehyde (trifluoroacetaldehyde) was prepared and characterized by NMR spectroscopy in solution. When switching to a saturated thiazolidin‐2‐ylidene, reaction with pentafluorobenzaldehyde afforded a new BI in solution (NMR spectroscopy). Attempts to crystallize the latter BI resulted in the isolation of a novel thiazolidin‐2‐ylidene dimer that had undergone rearrangement to a hexahydro1,4‐thiazino3,2‐b‐1,4‐thiazine.
Back to nature: In vitamin B1‐catalyzed umpolung, a Breslow intermediate (BI) is formed from an aromatic thiazolin‐2‐ylidene and the substrate aldehyde. The combination of a N‐Dipp‐substituted thiazolin‐2‐ylidene with pentafluorobenzaldehyde produced a BI, characterized by XRD. When trifluoroacetaldehyde was used, the first BI derived from a thiazolin‐2‐ylidene and an aliphatic aldehyde was generated, and characterized by NMR spectroscopy.
We herein report the ammonium salt‐catalyzed synthesis of chiral 3,3‐disubstituted isoindolinones bearing a heteroatom functionality in the 3‐position. A broad variety of differently substituted ...CF3S‐ and RS‐derivatives were obtained with often high enantioselectivities when using Maruoka's bifunctional chiral ammonium salt catalyst. In addition, a first proof‐of‐concept for the racemic synthesis of the analogous F‐containing products was obtained as well, giving access to one of the rare examples of a fairly stable α‐F‐α‐amino acid derivative.
The titanium complex of the cis‐1,2‐diaminocyclohexane (cis‐DACH) derived Berkessel‐salalen ligand is a highly efficient and enantioselective catalyst for the asymmetric epoxidation of terminal ...olefins with hydrogen peroxide (“Berkessel‐Katsuki catalyst”). We herein report that this epoxidation catalyst also effects the highly enantioselective hydroxylation of benzylic C−H bonds with hydrogen peroxide. Mechanism‐based ligand optimization identified a novel nitro‐salalen Ti‐catalyst of the highest efficiency ever reported for asymmetric catalytic benzylic hydroxylation, with enantioselectivities of up to 98 % ee, while overoxidation to ketone is marginal. The novel nitro‐salalen Ti‐catalyst also shows enhanced epoxidation efficiency, as evidenced by e.g. the conversion of 1‐decene to its epoxide in 90 % yield with 94 % ee, at a catalyst loading of 0.1 mol‐% only.
A cis‐1,2‐diaminocyclohexane (cis‐DACH) Ti salalen complex (R=NO2) was shown to efficiently catalyze enantioselective benzylic hydroxylations with H2O2 as oxidant. Tetralin and indane derivatives are converted to benzylic alcohols with up to 98 % ee. The overoxidation to ketone is negligible. Epoxidation reactions are similarly effective, with 1‐decene being converted to its epoxide in 90 % yield and 94 % ee, at 0.1 mol% catalyst loading.
We report the first generation and characterization of elusive Breslow intermediates derived from aromatic N‐heterocyclic carbenes (NHCs), namely benzimidazolin‐2‐ylidenes (NMR, X‐ray analysis) and ...thiazolin‐2‐ylidenes (NMR). In the former case, the diamino enols were generated by reaction of the free N,N‐bis(2,6‐diisopropylphenyl)‐ and N,N‐bis(mesityl)‐substituted benzimidazolin‐2‐ylidenes with aldehydes while the dimer of 3,4,5‐trimethylthiazolin‐2‐ylidene served as the starting material in the latter case. The unambiguous NMR identification of the first thiazolin‐2‐ylidene‐based Breslow intermediate rests on double 13C labeling of both the NHC and the aldehyde component. The acyl anion reactivity was confirmed by benzoin formation with excess aldehyde.
The key to carbene‐catalyzed umpolung may be seen in the generation and characterization of Breslow intermediates derived from aromatic N‐heterocyclic carbenes, ideally thiazol‐2‐ylidenes, as in vitamin B1. The first preparation and characterization of Breslow intermediates from aldehydes and a thiazolin‐2‐ylidene (A; NMR analysis), as well as benzimidazolin‐2‐ylidenes (B; NMR, X‐ray analysis), is reported.
In the present contribution, we investigated catalytically active mixtures of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and aqueous H2O2 by molecular dynamics simulations. It is clearly observable ...that the HFIP molecule strongly binds to the H2O2, which is necessary for the desired catalytic reaction to occur. Upon the addition of the substrate cyclooctene to the solution, this interaction is enhanced, which suggests that the catalytic activity is increased by the presence of the hydrocarbon. We could clearly observe the microheterogeneous structure of the mixture, which is the result of the separation of the hydroxyl groups, water, and H2O2 from the fluorinated alkyl moiety in the form of large domains, which span through large areas of the system. The hydrocarbon, however, does not fit into either one of these two microphases, and it forms separate aggregates in the macroscopically homogeneous liquid, creating thereby a triphilic mixture. The latter kinds of aggregates are mostly surrounded by the fluorous moieties, and therefore, the H2O2 has to move from the polar through the fluorous domain to be able to react with the cyclooctene. Accordingly, the present reaction should be described figuratively as a phase transfer or an interfacial reaction, rather than a homogeneous liquid-phase process.
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