Diaryl Methanes Research Articles

Discovery of Di(het)arylmethane and Dibenzoxanthene Derivatives as Potential Anticancer Agents.

A family of bifunctional dihetarylmethanes and dibenzoxanthenes is assembled via a reaction of acetals containing a 2-chloroacetamide moiety with phenols and related oxygen-containing heterocycles. These compounds demonstrated selective antitumor activity associated with the induction of cell apoptosis and inhibition of the process of glycolysis. In particular, bis(heteroaryl)methane containing two 4-hydroxy-6-methyl-2H-pyran-2-one moieties combine excellent in vitro antitumor efficacy with an IC50 of 1.7 µM in HuTu-80 human duodenal adenocarcinoma models with a high selectivity index of 73. Overall, this work highlights the therapeutic potential of dimeric compounds assembled from functionalized acetals and builds a starting point for the development of a new family of anticancer agents.

Synthesis of SGLT2 Inhibitors by Means of Fukuyama Coupling Reaction.

Disclosed herein is a novel and efficient synthesis of dapagliflozin and canagliflozin, the most advanced sodium glucose cotransporter 2 inhibitors (SGLT2 inhibitors), for the treatment of type 2 diabetes mellitus (T2DM). Per Ac-protected thioester was prepared by the treatment of per Ac d-gluconolactone with 1-dodecanethiol and iPrMgCl without affecting labile Ac-protecting groups. Aryl bromide (ArBr) was synthesized through reduction of diaryl ketone to diaryl methane by the TiCl4/NaBH4/DME-MeOH reduction system. Fukuyama coupling of the thioester with aryl zinc reagent prepared from ArBr gave a multifunctional aryl ketone at 40 °C in a high yield where the use of a limited amount of a mixed solvent (7.2 volumes (v), THF:toluene:DMF = 3v/4v/0.2v) was crucial to achieve the higher yield. After cleavage of the THP group, hydroxy ketone obtained was treated with methanesulfonic acid (MSA) in MeOH to give a methoxy-cyclized product in a single step and in a quantitative yield, which was allowed to silane reduction to furnish dapagliflozin in an excellent yield. By following the same procedure, canagliflozin was synthesized. The current synthetic method is featured by high yields, mild reaction conditions, and the use of inexpensive reagents and readily cleavable protecting groups.

Enantioselective Copper-Catalyzed Fukuyama Indole Synthesis from 2-Vinylphenyl Isocyanides.

Enantioenriched chiral indoles are of high interest for the pharmaceutical and agrochemical industries. Herein, we present an asymmetric Fukuyama indole synthesis through a mild and efficient radical cascade reaction to access 2-fluoroalkylated 3-(α-cyanobenzylated) indoles by stereochemical control with a chiral copper-bisoxazoline complex using 2-vinylphenyl arylisocyanides as radical acceptors and fluoroalkyl iodides as C-radical precursors. Radical addition to the isonitrile moiety, 5-exo-trig cyclization, and Cu-catalyzed stereoselective cyanation provide the targeted indoles with excellent enantioselectivity and good yields. Due to the similar electronic and steric properties of the two aryl substituents to be differentiated, the enantioselective construction of the cyano diaryl methane stereocenter is highly challenging. Mechanistic studies reveal a negative nonlinear effect which allows proposing a model to explain the stereochemical outcome. Scalability and potential utility of the enantioenriched 3-(α-cyanobenzylated) indoles as hubs for chiral tryptamines, indole-3-acetic acid derivatives, and triarylmethanes are demonstrated, and a formal synthesis of a natural product analogue is disclosed.

Synthesis of Novel Bromophenol with Diaryl Methanes-Determination of Their Inhibition Effects on Carbonic Anhydrase and Acetylcholinesterase.

In this work, nine new bromophenol derivatives were designed and synthesized. The alkylation reactions of (2-bromo-4,5-dimethoxyphenyl)methanol (7) with substituted benzenes 8-12 produced new diaryl methanes 13-17. Targeted bromophenol derivatives 18-21 were synthesized via the O-Me demethylation of diaryl methanes with BBr3. Moreover, the synthesized bromophenol compounds were tested with some metabolic enzymes such as acetylcholinesterase (AChE), carbonic anhydrase I (CA I), and II (CA II) isoenzymes. The novel synthesized bromophenol compounds showed Ki values that ranged from 2.53 ± 0.25 to 25.67 ± 4.58 nM against hCA I, from 1.63 ± 0.11 to 15.05 ± 1.07 nM against hCA II, and from 6.54 ± 1.03 to 24.86 ± 5.30 nM against AChE. The studied compounds in this work exhibited effective hCA isoenzyme and AChE enzyme inhibition effects. The results show that they can be used for the treatment of glaucoma, epilepsy, Parkinson's as well as Alzheimer's disease (AD) after some imperative pharmacological studies that would reveal their drug potential.

Palladium-Catalyzed Aryldifluoromethylation of Aryl Halides with Aryldifluoromethyl Trimethylsilanes.

Diaryl difluoromethanes are valuable targets for medicinal chemistry because they are bioisosteres of diaryl ethers and can function as replacements for diaryl methane, ketone, and sulfone groups. However, methods to prepare diaryl difluoromethanes are scarce, especially methods starting from abundant aryl halides. We report the Pd-catalyzed aryldifluoromethylation of aryl halides with aryldifluoromethyl trimethylsilanes (TMSCF2 Ar). The reaction occurs when the catalyst contains a simple, but unusual, dialkylaryl phosphine ligand that promotes transmetallation of the silane. Computational studies show that reductive elimination following transmetallation occurs with a low barrier, despite the fluorine atoms on the α-carbon, due to coordination of the difluorobenzyl π-system to palladium. The co-development of a cobalt-catalyzed synthesis of the silanes broadened the scope of the process including several applications to the synthesis biologically relevant diaryl difluoromethanes.

Palladium‐Catalyzed Aryldifluoromethylation of Aryl Halides with Aryldifluoromethyl Trimethylsilanes

AbstractDiaryl difluoromethanes are valuable targets for medicinal chemistry because they are bioisosteres of diaryl ethers and can function as replacements for diaryl methane, ketone, and sulfone groups. However, methods to prepare diaryl difluoromethanes are scarce, especially methods starting from abundant aryl halides. We report the Pd‐catalyzed aryldifluoromethylation of aryl halides with aryldifluoromethyl trimethylsilanes (TMSCF2Ar). The reaction occurs when the catalyst contains a simple, but unusual, dialkylaryl phosphine ligand that promotes transmetallation of the silane. Computational studies show that reductive elimination following transmetallation occurs with a low barrier, despite the fluorine atoms on the α‐carbon, due to coordination of the difluorobenzyl π‐system to palladium. The co‐development of a cobalt‐catalyzed synthesis of the silanes broadened the scope of the process including several applications to the synthesis biologically relevant diaryl difluoromethanes.

Lewis Acid-Promoted Typical Friedel-Crafts Reactions Using DMSO as a Carbon Source.

This study reports a mild and efficient synthetic protocol for the synthesis of symmetrical and unsymmetrical diarylmethanes (DAMs). Using DMSO as the C1 source and TMSOTf as the Lewis acid promoter, a series of functionalized symmetrical and unsymmetrical DAMs were synthesized in high yields. Gratifyingly, DMSO plays a dual role as a solvent and a C1 source and can also be replaced with its deuterated counterpart, DMSO-d6, enabling the incorporation of the -CD2 moiety into the diarylmethane skeleton. The developed approach has been applied to a wide range of substrates having various functional groups, and this protocol has also been extended to the synthesis of an anti-breast cancer agent and an anticoagulant agent using common feedstock compounds. In addition, the postulated mechanism has been explicitly demonstrated via control experiments.

Reductant‐Free Cross‐Electrophile Synthesis of Di(hetero)arylmethanes by Palladium‐Catalyzed Desulfinative C−C Coupling

AbstractAn efficient Pd‐catalyzed one‐pot desulfinative cross‐coupling to access medicinally relevant di(hetero)arylmethanes is reported. The method is reductant‐free, and involves a sulfinate transfer reagent and a Pd‐catalyst mediating the union of two electrophilic coupling partners; a (hetero)aryl halide and a benzyl halide. We establish for the first time that benzyl sulfinates, generated in situ, undergo efficient Pd‐catalyzed desulfinative cross‐coupling with (hetero)aryl halides to generate di(hetero)arylmethanes. The reaction can be extended to benzylic pseudohalides derived from benzyl alcohols. The reactions are straightforward to perform and scalable, and all reaction components are commercially available.

Reductant-Free Cross-Electrophile Synthesis of Di(hetero)arylmethanes by Palladium-Catalyzed Desulfinative C-C Coupling.

An efficient Pd‐catalyzed one‐pot desulfinative cross‐coupling to access medicinally relevant di(hetero)arylmethanes is reported. The method is reductant‐free, and involves a sulfinate transfer reagent and a Pd‐catalyst mediating the union of two electrophilic coupling partners; a (hetero)aryl halide and a benzyl halide. We establish for the first time that benzyl sulfinates, generated in situ, undergo efficient Pd‐catalyzed desulfinative cross‐coupling with (hetero)aryl halides to generate di(hetero)arylmethanes. The reaction can be extended to benzylic pseudohalides derived from benzyl alcohols. The reactions are straightforward to perform and scalable, and all reaction components are commercially available.

Reactions of Aminoacetals with C-Nucleophiles as a New Method for the Synthesis of Di(het)arylmethane Derivatives with a Taurine Fragment.

Based on the acid-catalyzed reaction of functionalized aminoacetals with C-nucleophiles, a series of new diarylmethane derivatives with a taurine fragment were synthesized, the structure of which was established by NMR spectroscopy method.

Construction of Di(hetero)arylmethanes Through Pd‐Catalyzed Direct Dehydroxylative Cross‐Coupling of Benzylic Alcohols and Aryl Boronic Acids Mediated by Sulfuryl Fluoride (SO2F2)

A practical Pd‐catalyzed direct dehydroxylative coupling of (hetero)benzylic alcohols with (hetero)arylboronic acids for the constructions of di(hetero)arylmethane derivatives under SO2F2 was described. This new method provided a strategically distinct approach to di(hetero)arylmethane derivatives from readily available and abundant benzylic alcohols under mild condition.

Deoxygenative cross-electrophile coupling of benzyl chloroformates with aryl iodides.

This work describes Ni-catalyzed cross-electrophile coupling of benzyl chloroformate derivatives with aryl iodides that generates a wide range of diaryl methane products. The mild reaction conditions merit the C-O bond radical fragmentation of benzyl chloroformates via halide abstraction or a single electron reduction by a Ni catalyst. This work offers a new substrate type for cross-electrophile couplings.

Copper‐Catalyzed (Di)Arylmethylation of Phosphorylamides Under Oxidative Conditions

A compatible and practical (di)arylmethylation of phosphorylamides was successfully accessed in the presence of copper iodide as the catalyst, azodiisobutyronitrile as the radical initiator, and di‐tert‐butyl peroxide as the oxidant. Both methylarenes and diaryl methanes were compatible under the oxidative conditions, enjoying broad functional groups tolerance (51 examples) and good efficiency (up to 90 % yields).

Transition-Metal-Free Selective C-H Benzylation of Tertiary Arylamines by a Dearomatization-Aromatization Sequence.

Due to the significance of hybrid systems in drug discovery, there is an urgent need to assemble multiple biologically active ingredients into a single molecule. Here, we report a general transition-metal-free selective C-H benzylation of tertiary arylamines in good to excellent yields with a broad substrate scope and high functional-group tolerance under mild conditions. Besides arylamines, some other benzene derivatives also readily furnished the corresponding diaryl methane derivatives with this protocol. A series of control experiments and theoretical calculations indicated that this transition-metal-free reaction is a dearomatization-aromatization process.

Cobalt-catalyzed oxidative arylmethylation of phosphorylamides

A cobalt-catalyzed strategy for N-arylmethylation of phosphorylamides was herein achieved with the assistance of azodiisobutyronitrile as the radical initiator and di-tert-butyl peroxide as the oxidant. Both methylarenes and diaryl methanes were compatible under the oxidative conditions, expressing broad substrate scope (51 examples) and high efficiency (up to 87% yield).

Transition-Metal-Free Suzuki-Type Cross-Coupling Reaction of Benzyl Halides and Boronic Acids via 1,2-Metalate Shift.

Cross-coupling of organoboron compounds with electrophiles (Suzuki-Miyaura reaction) has greatly advanced C-C bond formation and has been well received in medicinal chemistry. During the past 50 years, transition metals have played a central role throughout the catalytic cycle of this important transformation. In this process, chemoselectivity among multiple carbon-halogen bonds is a common challenge. In particular, selective oxidative addition of transition metals to alkyl halides rather than aryl halides is difficult due to unfavorable transition states and bond strengths. We describe a new approach that uses a single organic sulfide catalyst to activate both C(sp3) halides and arylboronic acids via a zwitterionic boron "ate" intermediate. This "ate" species undergoes a 1,2-metalate shift to afford Suzuki coupling products using benzyl chlorides and arylboronic acids. Various diaryl methane analogues can be prepared, including those with complex and biologically active motifs. The reactions proceed under transition-metal-free conditions, and C(sp2) halides, including aryl bromides and iodides, are unaffected. The orthogonal chemoselectivity is demonstrated in the streamlined synthesis of highly functionalized diaryl methane scaffolds using multi-halogenated substrates. Preliminary mechanistic experiments suggest both the sulfonium salt and the sulfur ylide are involved in the reaction, with the formation of sulfonium salt being the slowest step in the overall catalytic cycle.

Carbene-catalyzed enantioselective oxidative coupling of enals and di(hetero)arylmethanes.

Di(hetero)arylmethane is a unique structural motif for natural and synthetic functional molecules. To date, it remains challenging to functionalize the diaryl methyl sp3 carbon-hydrogen bond directly in an enantioselective manner. This is likely due to the relatively inert nature of the carbon-hydrogen bond and the difficult enantiofacial discrimination of two sterically similar aryl substituents. Here we disclose an N-heterocyclic carbene-catalyzed direct oxidative coupling of enals and di(hetero)arylmethanes. Our method allows for highly enantioselective transformation of diaryl methanes and quick access to benzimidazole fused lactams.

Palladium-catalysed synthesis of triaryl(heteroaryl)methanes

Tetraarylmethane derivatives are desirable for a variety of applications, but difficult to access with modern C–C bond-forming reactions. Here we report a straightforward method for palladium-catalysed arylation of aryl(heteroaryl)methanes and diaryl(heteroaryl)methanes with aryl chlorides. This reaction enables introduction of various aryl groups to construct triaryl(heteroaryl)methanes via a C–H functionalization in good to excellent yield, and represents the first step towards a general transition metal catalysed synthesis of tetraarylmethanes.

One-pot borylation/Suzuki-Miyaura sp2-sp3 cross-coupling.

We describe the first one-pot borylation/Suzuki-Miyaura sp2-sp3 cross-coupling between readily available aryl (pseudo)halides and activated alkyl chlorides. This method streamlines the synthesis of diaryl methanes, α-aryl carbonyls and allyl aryl compounds, substructures that are commonly found in life changing drug molecules.

Nickel-Catalyzed Reductive Cross-Coupling of Benzyl Halides with Aryl Halides

Systematic studies of the coupling of benzylic with aryl halides are presented. The optimized reaction conditions for electron-deficient­ aryl halides cannot be applied to the electron-rich or neutral counterparts, and vice versa. The excellent functional group tolerance and broad substrate scope may enable the current work to be useful for the construction of diaryl methane products.