Benzyl Iodide Research Articles

Development of Adagrasib’s Commercial Manufacturing Route

A commercial route to adagrasib (1) was developed to support clinical and commercial needs. Yield was improved to 32% over six chemical steps. A doubly regioselective SNAr reduced consumption of a chiral intermediate, reaction optimization led to parts per million palladium catalysis, and a new method to deprotect Cbz-groups were developed to mitigate risk associated with benzyl iodide.

Preparation of Ring-Methoxylated Arylnitromethanes by the Victor Meyer Reaction

AbstractEasily accessible and stable ring-methoxylated benzyl chlorides react with AgNO2 to give mixtures of the corresponding arylnitromethanes and nitrite esters. A modified approach for the isolation of arylnitromethanes is described, which represents a valuable improvement of the established Victor Meyer reaction. The isolation technique, which involves reaction of the nitrite ester with urea in methanol, allows the desired arylnitromethanes to be isolated, without loss, in 29–75% yields, and generates the corresponding recyclable benzyl alcohols. Unexpectedly, ring-methoxylated benzyl iodides cannot be used because they are not sufficiently stable and produce tars under the developed reaction conditions.

Synthesis of Fused pyrazolo[4,3‐c]quinolines through KI‐Promoted Cyclization of Pyrazole‐arylamines and Benzyl Bromide

AbstractA simple and highly efficient protocol was developed for the formation of pyrazolo[4,3‐c]quinolines starting from 2‐(1H‐pyrazol‐5‐yl)anilines and benzyl bromide in the presence of KI, affording desired products in moderate to good yields. The reaction showed good tolerance for a range of substrates with variable substituents. In this methodolgy, benzyl bromide proved to be an available C1 synthon in organic synthesis. Moreover, benzyl bromide can be replaced with benzyl iodide to synthesize pyrazolo[4,3‐c]quinoline derivatives, and benzyl chloride could not apply in this reaction system.

Indium-Catalyzed Formal Carbon-Halogen Bond Insertion: Synthesis of α-Halo-α,α-disubstituted Esters from Benzylic Halides and Diazo Esters.

One-carbon-unit insertion into carbon-halogen (C-X) bonds accompanied by the formation of a new C-X bond and carbon-chain elongation is a powerful synthetic method of complex organohalides. Herein, we developed an indium trihalide catalyzed formal insertion of diazo esters into a C-X (X = Cl, Br, I) bond. In the present system, the reactions of α-aryl diazo esters with benzylic chlorides, bromides, and iodides yielded α-chloro, α-bromo, and α-iodo esters, respectively.

Synthesis and crystal structure of (E)-2-benzyl-1,3-di-phenyl-iso-thio-uronium iodide.

In the title mol-ecular salt, C20H19N2S+·I-, prepared by the reaction of 1,3-di-phenyl-thio-urea and benzyl iodide, the C-S-C thio-ether bond angle is 101.66 (9)° and electrons are delocalized over the N+= C-N skeleton. The dihedral angle between the aromatic rings attached to the N atoms is 40.60 (9)°. In the crystal, N-H⋯I hydrogen bonds link the components into [100] chains.

External Catalyst‐Free Oxidation of Benzyl Halides to Benzoic Acids Using NaOH/TBHP in Water

AbstractAn efficient and metal‐free methodology for the oxidation of benzyl halides to benzoic acids using an inexpensive and green oxidant (TBHP) in aqueous basic medium has been developed. This protocol offers an excellent way to avoid adding catalysts and involves the use of an in‐situ generated halide ion as catalyst. It is also the first report on the oxidation of benzyl iodides to benzoic acids. A series of carboxylic acids were prepared from benzyl halides in high yields under mild reaction conditions by this method which does not require chromatographic purification. Gram scale reactions for the synthesis of the carboxylic acids in good yields have been successfully carried out using benzyl chloride, bromide and iodide. As an industrial application, the synthesis of a key monomer used for the synthesis of polyethylene terephthalate (PET), i. e., terephthalic acid (PTA), has also been accomplished in good yields.

Conversion of Aryl Aldehydes to Benzyl Iodides and Diarylmethanes by H3PO3/I2.

For the first time, H3PO3 was used as both the reducing reagent and the promotor in the reductive benzylation reactions with aryl aldehydes. By using a H3PO3/I2 combination, various aromatic aldehydes underwent iodination reactions and Friedel-Crafts type reactions with arenes via benzyl iodide intermediates, readily producing benzyl iodides and diarylmethanes in good yields. Intramolecular cyclization reactions also took place, giving the corresponding cyclic compounds. This new strategy features easy-handling, low-cost, and metal-free conditions.

Construction of sterically congested oxindole derivatives via visible-light-induced radical-coupling.

The oxindole scaffold represents an important structural feature in many natural products and pharmaceutically relevant molecules. Herein, we report a visible-light-induced modular methodology for the synthesis of complex 3,3′-disubstituted oxindole derivatives. A library of valuable fluoroalkyl-containing highly sterically congested oxindole derivatives can be synthesized by a catalytic three-component radical coupling reaction under mild conditions (metal & photocatalyst free, >80 examples). This strategy shows high functional group tolerance and broad substrate compatibility (including a wide variety of terminal or non-terminal alkenes, conjugated dienes and enynes, and a broad array of polyfluoroalkyl iodide and oxindoles), which enables modular modification of complex drug-like compounds in one chemical step. The success of solar-driven transformation, large-scale synthesis, and the late-stage functionalization of bioactive molecules, as well as promising tumor-suppressing biological activities, highlights the potential for practical applications of this strategy. Mechanistic investigations, including a series of control experiments, UV-vis spectroscopy and DFT calculations, suggest that the reaction underwent a sequential two-step radical-coupling process and the photosensitive perfluoroalkyl benzyl iodides are key intermediates in the transformation.

Solar and visible-light active nano Ni/g-C3N4 photocatalyst for carbon monoxide (CO) and ligand-free carbonylation reactions

In this study, we investigate the amino and alkoxycarbonylation reaction between various substituted aryl halides, benzyl iodides, and iodocyclohexane with different types of amines and alcohols in the absence of carbon monoxide gas and ligands.

Automated synthesis of 18F radiolabelled indole containing Oncrasin-like molecules; a comparison of iodonium salts and boronic ester chemistry

BackgroundOncrasin-1 is a small molecule which was identified from a screen of KRAS mutant cancer cells and has shown specificity for KRAS mutant cell killing. We aimed to develop a radiolabelled form of Oncrasin-1 to enable in-vivo imaging of mutant KRAS expression in malignant tumours. This work outlines the synthesis of 3 fluorinated derivatives and development of iodonium salt and boronic ester precursors for radiolabelling with the 18F isotope.ResultsIn our hands, synthesis of iodonium salts were not easily accessible due to the 3-carbaldehyde indole structure being preferentially oxidized by conditions required for iodonium salt formation, rather than benzyl iodide. Synthesis and radiolabelling of boronic acid pinacol ester precursors were successful, with the products being obtained in yields of 10.76% ± 0.96% (n = 5), 14.7% ±8.58% (n = 3) and 14.92% ±3.9% (n = 3) for 18F KAM001, 18F KAM002 and 18F KAM003 respectively, with radiochemical purity of greater than 99%.ConclusionsThe successful synthesis of these tracers has been undertaken utilizing boronic ester radio-fluorination methods and will allow for investigation of Oncrasin based molecules as potential diagnostics for cancers expressing mutant KRAS protein.

Continuous Flow Preparation of (Hetero)benzylic Lithiums via Iodine-Lithium Exchange Reaction under Barbier Conditions.

Herein we report the generation of benzylic lithiums via an iodine-lithium exchange reaction on benzylic iodides performed in continuous flow using tBuLi as the exchange reagent. The resulting benzylic lithium species are trapped in situ by carbonyl electrophiles under Barbier conditions, resulting in benzylic secondary and tertiary alcohols. This flow procedure further allows the generation of highly reactive heterobenzylic lithium compounds, which are difficult to generate under batch conditions. A general scale-up was possible without further optimization.

Molecule-Induced p-Doping in Perovskite Nanocrystals Enables Efficient Color-Saturated Red Light-Emitting Diodes.

Color-saturated red light-emitting diodes (LEDs) with emission wavelengths at around 620-640 nm are an essential part of high-definition displays. Metal halide perovskites with very narrow emission linewidth are promising emitters, and rapid progress has been made in perovskite-based LEDs (PeLEDs); however, the efficiency of the current color-pure red PeLEDs-still far lags behind those of other-colored ones. Here, a simple but efficient strategy is reported to gradually down-shift the Fermi level of perovskite nanocrystals (NCs) by controlling the interaction between NCs and their surface molecular electron acceptor-benzyl iodide with aromatic rings-and realize p-doping in the color-saturated 625 nm emitting NCs, which significantly reduces the hole injection barrier in devices. Besides, both the luminescence efficiency and electric conductivity of perovskite NCs are enhanced as additional advantages as the result of surface defects passivation. As a result, the external quantum efficiency for the resulting LED is increased from 4.5% to 12.9% after benzyl iodide treatment, making this device the best-performing color-saturated red PeLED so far. It is further found that the hole injection plays a more critical role than the photoluminescence efficiency of perovskite emitter in determining the LED performance, which implies design principles for efficient thin-film planar LEDs.

Rheological Properties of Covalent Adaptable Networks with 1,2,3-Triazolium Cross-Links: The Missing Link between Vitrimers and Dissociative Networks

Vitrimers, in stringent contrast to dissociative networks, involve associative covalent exchanges and remain fully cross-linked at all temperatures. However, we have previously reported on poly(1,2,3-triazolium) dynamic networks that exhibit linear rheological characterization indistinguishable from vitrimers although being based on a dissociative covalent exchange process, i.e., deN -alkylation and re-N-alkylation reactions. Herein, we highlight the main features of dissociative and associative covalent adaptable networks (CANs) and discuss their respective linear rheological behaviors. After giving a detailed overview of the extent and potential of dynamic polymer networks having 1,2,3-triazolium cross-links in particular and CANs involving trans-N-alkylation exchanges in general, we perform a detailed rheological comparative characterization of previously described aliphatic 1,2,3-triazolium-based dynamic networks and a new bicomponent thermosetting system issued from the mixing of linear polystyrene chains having complementary benzyl iodide and 1,2,3-triazole pendent groups. We propose a simple but comprehensive rheological characterization methodology that enables proper comparison between all types of CANs, i.e., vitrimers and dissociative networks. Owing to the combination of a high glass transition temperature dynamic network and fast trans-N-alkylation exchanges in this new dissociative network, it is possible to characterize both glass transition and network relaxation with single rheological experiments. We provide clear experimental evidence that although located within a narrow temperature range, the temperature dependences of these two transitions are distinct and follow WLF and Arrhenius models, respectively.

Visible-Light-Induced Charge Transfer Enables Csp3-H Functionalization of Glycine Derivatives: Access to 1,3-Oxazolidines.

A photoredox catalyst free, visible-light-induced aerobic oxidative [2 + 3] cycloaddition reaction between glycine derivatives and styrene oxides has been disclosed that provides an efficient approach for the rapid synthesis of 1,3-oxazolidines under mild conditions. This photoinduced process is enabled by the formation of an electron donor-acceptor complex between glycine derivatives and benzyl iodides.

A Facile One‐Pot Synthesis of 2,2,2‐Trichloroacetates Through Acid‐Catalyzed Deimination and Its Applications

AbstractA novel one‐pot approach for the synthesis of trichloroacetates is described. Use of inexpensive, commercially available trichloroacetonitrile as a trichloroacyl source has made this protocol have more industrial applications. This one‐pot approach is applicable to a wide range of alcohols as demonstrated by 28 examples with good to excellent yields in the order of 93%. Trichloroacetates were characterized by infrared, NMR spectra and further the structure of 2‐(1,3‐dioxoisoindolin‐2‐yl)ethyl‐2,2,2‐trichloroacetate was confirmed by single‐crystal X‐ray diffraction. Moreover, benzyl trichloroacetates synthesized were converted into corresponding benzyl iodides in good yields (51‐70%). In addition, bypassing harsh reagents, use of cheaper, commercially available sodium iodide as nucleophile and mild reaction conditions are some of practical features of this methodology.

Forming Benzylic Iodides via a Nickel Catalyzed Diastereoselective Dearomative Carboiodination Reaction of Indoles

AbstractA diastereoselective dearomative carboiodination reaction is reported. We report a novel metal‐catalyzed approach to install reactive secondary benzylic iodides. Utilizing the unique reactivity of nickel, we have expanded the carboiodination reaction to non‐activated aromatic double bonds forming a previously unattainable class of iodides. We also report a broadly applicable method to avoid the use of a metallic reducing agent by utilizing an alkyl phosphite as the ligand. The reaction is thought to proceed through a syn intramolecular carbonickelation across a 2‐substituted indole followed by a diastereoretentive reductive elimination of the carbon−iodine bond. The complex iodinated indolines generated in the reaction were obtained in moderate to good yields and good to excellent diastereoselectivity. The products were easily functionalized by a variety of synthetic methods.

Forming Benzylic Iodides via a Nickel Catalyzed Diastereoselective Dearomative Carboiodination Reaction of Indoles.

A diastereoselective dearomative carboiodination reaction is reported. We report a novel metal-catalyzed approach to install reactive secondary benzylic iodides. Utilizing the unique reactivity of nickel, we have expanded the carboiodination reaction to non-activated aromatic double bonds forming a previously unattainable class of iodides. We also report a broadly applicable method to avoid the use of a metallic reducing agent by utilizing an alkyl phosphite as the ligand. The reaction is thought to proceed through a syn intramolecular carbonickelation across a 2-substituted indole followed by a diastereoretentive reductive elimination of the carbon-iodine bond. The complex iodinated indolines generated in the reaction were obtained in moderate to good yields and good to excellent diastereoselectivity. The products were easily functionalized by a variety of synthetic methods.

New convergent one pot synthesis of amino benzyl ethers bearing a nitrogen-containing bicycle

We report herein a new convergent one pot method for the synthesis of amino benzyl ethers containing a bicyclic amine, derived from different substituted benzyl alcohols and bicyclic amino alcohols such as tropine, pseudotropine, and 3-quinuclidinol, using chlorotrimethylsilane and sodium iodide. In order to avoid the competitive reaction with the nitrogen atom, a solution of the separately prepared alkoxide of tropine, pseudotropine, and 3-quinuclidinol was added to the preformed substituted benzyl iodides and allowed to reflux at 90 °C for 15 h under nitrogen atmosphere. This method provides an efficient alternative of the preparation of amino benzyl ethers in organic synthesis with good yields in comparison with existed methods.

A new HPLC-UV derivatization approach for the determination of potential genotoxic benzyl halides in drug substances.

Benzyl halides, widely used as alkylation reagents in drug synthesis, are potential genotoxic impurities (PGTIs) required to be controlled at trace levels. However, the existing analytical methods for benzyl halides often suffer from matrix interferences or low derivatization efficiency of benzyl chlorides. In this paper, a simple derivatization HPLC-UV method was developed for the analysis of these residual trace benzyl halides in drug substances. 1-(4-Nitrophenyl) piperazine (4-NPP) was selected as a new derivatization reagent because it shifted well the benzyl halides derivatives away to the near visible range (392 nm), which could minimize the matrix interferences from the drug substances and related impurities. Meanwhile, potassium iodide (KI) was used to convert the mixed benzyl halides into benzyl iodides before derivatization. The derivatization parameters were also optimized using the design of experiments (DoE) for achieving the best reaction efficiency. The results showed that the new approach had high specificity and sensitivity, and the LOQs were 7–9 μg g−1 relative to 5 mg mL−1 antipyrine and 17.5–22.5 μg g−1 relative to 2 mg mL−1 oroxylin A. The method is a valuable alternative for the determination of residual benzyl halides in the drug substances.

Assessing the effectiveness of oxidative approaches for the synthesis of aldehydes and ketones from oxidation of iodomethyl group

Owing to excellent selectivity, high yield and stability towards over-reduction and over-oxidation, one of the impressive approaches to synthesize aldehydes and ketones is the oxidation of halomethyl groups. Numerous halomethyl oxidation-based methodologies to afford aldehydes and ketones are disclosed in the literature. Mostly, chloromethyl or bromomethyl group containing substrates have been used in the literature for performing oxidation. There are negligible data available in the literature that addresses the use of iodomethyl group containing substrates for transformation to aldehydes and ketones. In this research work, 110 reactions have been carried out to construct aldehydes and ketones from oxidation of iodomethyl group in benzylic iodides and allylic iodides using numerous well-known approaches reported in the literature. The classical approaches under observation include Sommelet oxidation, Krohnke oxidation, sodium periodate-mediated oxidative protocol, manganese dioxide-based oxidative approach, Kornblum oxidation and Hass–Bender oxidation. The eco-friendly approaches under observation include periodic acid-based IL protocol, periodic acid in vanadium pentoxide-mediated IL method, hydrogen peroxide in vanadium pentoxide-based approach and bismuth nitrate-promoted IL technique. In this investigation, yield, recyclability, cost-effectiveness, eco-friendliness and over-oxidation are the main parameters which are under observation. Among all these investigated techniques, periodic acid-based IL protocol, periodic acid in vanadium pentoxide-mediated IL method and hydrogen peroxide in vanadium pentoxide-based approach (aka. Chunbao oxidation protocol) were found to be highly efficient due to the following reasons: these approaches (1) provide excellent yields, (2) do not lead towards over-oxidation, (3) show good recyclability, (4) demonstrate high thermal stability and negligible flammability, and (5) require no special handling.