Subsequent Alkylation Research Articles

Synthesis of N-Alkyl-1,3-dihydro-2,1-benzisoxazoles.

We describe a practical method for the synthesis of various substituted N-alkyl-1,3-dihydro-2,1-benzisoxazoles and their 2,1-benzisoxazolone precursors starting from readily available methyl 2-nitrobenzoates. The method entails partial nitro reduction with hydrazine and rhodium on carbon to give the hydroxylamines, followed by base-mediated cyclization to give the corresponding benzisoxazol-3(1H)-ones. Subsequent alkylation is conducted under basic conditions and is followed by reduction to the target 1,3-dihydrobenzisoxazoles, achieved with lithium aluminum hydride in the presence of trimethylsilyl chloride.

Quantum chemical calculations of nitrosamine activation and deactivation pathways for carcinogenicity risk assessment.

N-nitrosamines and nitrosamine drug substance related impurities (NDSRIs) became a critical topic for the development and safety of small molecule medicines following the withdrawal of various pharmaceutical products from the market. To assess the mutagenic and carcinogenic potential of different N-nitrosamines lacking robust carcinogenicity data, several approaches are in use including the published carcinogenic potency categorization approach (CPCA), the Enhanced Ames Test (EAT), in vivo mutagenicity studies as well as read-across to analogue molecules with robust carcinogenicity data. We employ quantum chemical calculations as a pivotal tool providing insights into the likelihood of reactive ion formation and subsequent DNA alkylation for a selection of molecules including e.g., carcinogenic N-nitrosopiperazine (NPZ), N-nitrosopiperidine (NPIP), together with N-nitrosodimethylamine (NDMA) as well as non-carcinogenic N-nitrosomethyl-tert-butylamine (NTBA) and bis (butan-2-yl) (nitros)amine (BBNA). In addition, a series of nitroso-methylaminopyridines is compared side-by-side. We draw comparisons between calculated reaction profiles for structures representing motifs common to NDSRIs and those of confirmed carcinogenic and non-carcinogenic molecules with in vivo data from cancer bioassays. Furthermore, our approach enables insights into reactivity and relative stability of intermediate species that can be formed upon activation of several nitrosamines. Most notably, we reveal consistent differences between the free energy profiles of carcinogenic and non-carcinogenic molecules. For the former, the intermediate diazonium ions mostly react, kinetically controlled, to the more stable DNA adducts and less to the water adducts via transition-states of similar heights. Non-carcinogenic molecules yield stable carbocations as intermediates that, thermodynamically controlled, more likely form the statistically preferred water adducts. In conclusion, our data confirm that quantum chemical calculations can contribute to a weight of evidence approach for the risk assessment of nitrosamines.

Copper-Catalyzed Asymmetric Remote C(sp3)-H Alkylation of N-Fluorocarboxamides with Glycine Derivatives and Peptides.

Saturated hydrocarbon bonds are ubiquitous in organic molecules; to date, the selective functionalization of C(sp3)-H bonds continues to pose a notorious difficulty, thereby garnering significant attention from the synthetic chemistry community. During the past several decades, a wide array of powerful new methodologies has been developed to enantioselectively modify C(sp3)-H bonds that is successfully applied in asymmetric formation of diverse bonds, including C-C, C-N, and C-O bonds; nevertheless, the asymmetric C(sp3)-H alkylation is elusive and, therefore, far less explored. In this work, we report a direct and robust strategy to construct highly valuable enantioenriched unnatural α-amino acid (α-AA) cognates and peptides by a copper-catalyzed enantioselective remote C(sp3)-H alkylation of N-fluorocarboxamides and readily accessible glycine esters under ambient conditions. The key to success lies in the optically active Cu catalyst generated through the coordination of glycine derivatives to enantiopure bisphosphine/Cu(I) species, which is beneficial to the single electronic reduction of N-fluorocarboxamides and the subsequent stereodetermining alkylation. More importantly, all types (primary, secondary, tertiary, and even α-oxy) of δ-C(sp3)-H bonds could be site- and stereospecifically activated by the kinetically favored 1,5-hydrogen atom transfer (1,5-HAT) step.

Total Synthesis of (±)-20-epi-Kopsiyunnanine K: A Domino and Stereocontrolled Approach.

A one-pot route to a novel azepane-fused tetrahydro-β-carboline framework from tryptyl-4-pentenamide derivatives has been developed, featuring the Rh-catalyzed hydroformylation double cyclization. Subsequent alkylation in the tetracyclic system proceeded stereoselectively to form a quaternary carbon. The synthesis of (±)-20-epi-kopsiyunnanine K was accomplished through the strategy.

Stereoselective Control of the Cu Activation of β,β-Diboryl Acrylates for Allylic Coupling Protocols with Concomitant Lactonization.

The key to a successful C-B activation is to discriminate between two geminal boryl moieties that are exposed to the same reaction conditions. Here we describe a stereoselective C-B activation of β,β-diboryl acrylates forming exclusively the (Z)-α-borylalkenyl copper(I) key intermediate, for subsequent allylic alkylation reactions. The new borylated (Z)-skipped dienoates followed a feasible iodo-lactonization sequence for the preparation of borylated lactone cores, which can be used in drug discovery.

Enantio‐ and Diastereoselective NiH‐Catalyzed Hydroalkylation of Enamides or Enecarbamates with Racemic α‐Bromoamides**

AbstractCatalytic methods which control multiple stereogenic centers simultaneously are highly desirable in modern organic synthesis and chemical manufacturing. Herein, we report a regio‐, enantio‐, and diastereoselective NiH‐catalyzed hydroalkylation process which proceeds with simultaneous control of vicinal stereocenters originating from two readily accessible partners, prochiral internal alkenes (enamides or enecarbamates) and racemic alkyl electrophiles (α‐bromoamides or Katritzky salts). This reaction produces high‐value β‐aminoamides and their derivatives under mild conditions and with precise selectivity. Preliminary studies of the mechanism indicate that the reaction involves an enantioselective syn‐hydronickelation to generate an enantiomerically enriched alkylnickel(II) species. Subsequent enantioconvergent alkylation with a racemic alkyl electrophile generates the desired product as a single stereoisomer.

Enantio- and Diastereoselective NiH-Catalyzed Hydroalkylation of Enamides or Enecarbamates with Racemic α-Bromoamides.

Catalytic methods which control multiple stereogenic centers simultaneously are highly desirable in modern organic synthesis and chemical manufacturing. Herein, we report a regio-, enantio-, and diastereoselective NiH-catalyzed hydroalkylation process which proceeds with simultaneous control of vicinal stereocenters originating from two readily accessible partners, prochiral internal alkenes (enamides or enecarbamates) and racemic alkyl electrophiles (α-bromoamides or Katritzky salts). This reaction produces high-value β-aminoamides and their derivatives under mild conditions and with precise selectivity. Preliminary studies of the mechanism indicate that the reaction involves an enantioselective syn-hydronickelation to generate an enantiomerically enriched alkylnickel(II) species. Subsequent enantioconvergent alkylation with a racemic alkyl electrophile generates the desired product as a single stereoisomer.

Benzimidazole-diamide (bida) Pincer Chromium Complexes: Structures and Reactivity.

Serendipitous discovery of bida (i.e., N1-Ar-N2-((1-Ar-1-benzo[d]imidazol-2-yl)methyl)benzene-1,2-diamide; Ar = 2,6-iPr-C6H3), a potentially redox noninnocent, hemilabile pincer ligand with a methylene group that may facilitate proton/H atom reactivity, prompted its investigation. Chromium was chosen for study due to its multiple stable oxidation states. Disodium salt (bida)Na2(THF)n was prepared by thermal rearrangement of (dadi)Na2(THF)4 (i.e., (N,N'-di-2-(2,6-diisopropylphenylamine)phenylglyoxaldiimine)-Na2(THF)4). Salt metathesis of (bida)Na2(THF)n (generated in situ) with CrCl3(THF)3 or Cl3V═NAr (Ar = 2,6-iPr2C6H3) afforded (bida)CrCl(THF) (1-THF) and (bida)ClV═NAr, respectively. Substitutions provided (bida)CrCl(PMe2Ph) (1-PMe2Ph) and (bida)CrR(THF) (2-R, where R = Me, CH2CMe2Ph (Nph)). Oxidation of 1-THF with ArN3 (Ar = 2,6-iPr2C6H3) or AdN3 (Ad = 1-adamantyl) generated (bida)ClCr═NAr (3═NAr) and (bida)ClCr═NAd (3═NAd) and subsequent alkylation converted these to (bida)R'Cr═NR (R' = Me, R = Ad, Ar, 5═NR; R' = CH2CMe2Ph (Nph), R = Ad, Ar, 6═NR). In contrast, the addition of AdN3 to 2-Nph gave the insertion product (bida)Cr(κ2-N,N-ArN3Nph) (7). Addition of N-chlorosuccinimide to 1-THF produced (bia)CrCl2(THF) (8), where bia is the pincer derived via hydrogen atom loss from bida methylene. A similar HAT afforded (bia)ClCr(CNAr')2 (9, Ar' = 2,6-Me2C6H3) when 3═NAd was exposed to Ar'NC. An empirical equation of charge was applied to each bida species, whose metric parameters are unchanging despite formal oxidation state conversions from Cr(III) to Cr(V). Calculations and Mulliken spin density assessments reveal several situations in which antiferromagnetic (AF) coupling and admixtures of integer ground states (GSs) describe a complicated electronic structure.

Tandem Dearomatization/Enantioselective Allylic Alkylation of Pyridines.

Herein, we report a multistep one-pot reaction of substituted pyridines leading to N-protected tetrahydropyridines with outstanding enantioselectivity (up to 97% ee). An iridium(I)-catalyzed dearomative 1,2-hydrosilylation of pyridines enables the use of N-silyl enamines as a new type of nucleophile in a subsequent palladium-catalyzed asymmetric allylic alkylation. This telescoped process overcomes the intrinsic nucleophilic selectivity of pyridines to synthesize enantioenriched, C-3-substituted tetrahydropyridine products that have been otherwise challenging to access.

Enriching Cysteine-Containing Peptides Using a Sulfhydryl-Reactive Alkylating Reagent with a Phosphonic Acid Group and Immobilized Metal Affinity Chromatography.

The reduction of disulfide bonds and their subsequent alkylation are commonplace in typical proteomics workflows. Here, we highlight a sulfhydryl-reactive alkylating reagent with a phosphonic acid group (iodoacetamido-LC-phosphonic acid, 6C-CysPAT) that facilitates the enrichment of cysteine-containing peptides for isobaric tag-based proteome abundance profiling. Specifically, we profile the proteome of the SH-SY5Y human cell line following 24 h treatments with two proteasome inhibitors (bortezomib and MG-132) in a tandem mass tag (TMT)pro9-plex experiment. We acquire three datasets─(1) Cys-peptide enriched, (2) the unbound complement, and (3) the non-depleted control─and compare the peptides and proteins quantified in each dataset, with emphasis on Cys-containing peptides. The data show that enrichment using 6C-Cys phosphonate adaptable tag (6C-CysPAT) can quantify over 38,000 Cys-containing peptides in 5 h with >90% specificity. In addition, our combined dataset provides the research community with a resource of over 9900 protein abundance profiles exhibiting the effects of two different proteasome inhibitors. Overall, the seamless incorporation of alkylation by 6C-CysPAT into a current TMT-based workflow permits the enrichment of a Cys-containing peptide subproteome. The acquisition of this "mini-Cys" dataset can be used to preview and assess the quality of a deep, fractionated dataset.

Microwave-Assisted Cu-Catalyzed Diaryletherification for Facile Synthesis of Bioactive Prenylated Diresorcinols

Prenylated diresorcinols exhibit various bioactivities, including cytotoxic, antibacterial, and antifungal activities. Therefore, establishing facile and efficient synthetic routes for prenylated diresorcinols facilitates their development as chemical probes or drugs with a novel mode of action. In this study, microwave-assisted copper catalysis was explored as a cost-effective and environmentally friendly method for the cross-coupling of sterically hindered ortho-prenylated phenols and aryl halides to produce bioactive prenylated diresorcinols, diorcinol I and leotiomycene B. Notable advantages of microwave-assisted catalysis include not only operational simplicity and rapid heating but also shorter reaction times and higher chemical yields. In addition, highly regioselective prenylation of phenol was achieved for the preparation of ortho-prenyl phenol via directed lithiation and subsequent alkylation. This study provides valuable insights for the preparation of other bioactive prenylated diresorcinols. Furthermore, considering that prenylated benzenoids are biosynthetic precursors of various polycyclic natural products, this synthetic route could be expanded to more complex bioactive compounds possessing diaryl ethers.

Radical aminoalkylation of maleimides with alkylamines and alkanes

A meaningful copper‐catalyzed chemo‐selective oxidative alkylamination of maleimides with secondary alkyl amines and simple alkanes has been developed. This transformation exhibits excellent compatibility with an array of polyfunctionalized organic amines and inactivated alkanes, modular synthesis of 3‐carbo‐4‐amino maleimides under simple, and efficient catalytic systems. Detailed mechanistic studies support the formation of 3‐amino maleimides and alkyl radical intermediates and their subsequent radical alkylation in the reaction process.

Mechanistic and Synthetic Studies of Biaryl Birch Reductions

AbstractThe Birch reduction of biaryls generally converts one of the two arenes into a cyclohexa-1,4-diene. Biaryls are more reactive than monocyclic arenes under the Birch conditions. Unlike the reduction of monocyclic arenes, biaryl reduction proceeds through two consecutive electron transfer steps before the protonation of the dianion intermediate. The biaryl reductions and subsequent alkylations in one pot rapidly increase the molecular complexity and thus have been used in the synthesis of natural products and drug-like molecules.1 Introduction2 The Physical Organic Chemistry of the Birch Reduction of Biaryls3 Biaryls as the Mediators of Electron Transfer4 Methods for the Dissolving-Metal Reduction of Biaryls5 Intercepting the Biaryl Reduction Intermediates with Electrophiles6 Synthetic Applications of the Dissolving-Metal-Mediated Reductions of Biaryls7 Outlook

Oxidative Fluorination of Selenium and Tellurium Compounds using a Thermally Stable Phosphonium SF5 - Salt Accessible from SF6.

Fluorinated group 16 moieties are attractive building blocks in synthetic chemistry but only few synthetic methods are available to prepare them. Herein, we report a new oxidative fluorination reagent capable of stabilizing reactive fluorinated anions. It consists of an SF5 - anion and a chemically inert phosphonium cation and is exceptionally thermally stable. Accordingly, it was used to generate the SeF5 - and TeF5 - anions from the elemental chalcogens and to prepare the unknown tetrafluoro(phenyl)-λ5 -selenate PhSeF4 - and -tellurate PhTeF4 - from the corresponding diphenyl dichalcogenides. In addition, we show that further derivatization of [PhTeF4 ]- by oxidation to trans-PhTeF4 O- and subsequent alkylation gives access to a new class of trans-(alkoxy)(phenyl)tetrafluoro-λ6 -tellanes (trans-PhTeF4 OR), thus providing an approach to introduce the functional group into organic molecules.

Oxidative Fluorination of Selenium and Tellurium Compounds using a Thermally Stable Phosphonium SF5−Salt Accessible from SF6

AbstractFluorinated group 16 moieties are attractive building blocks in synthetic chemistry but only few synthetic methods are available to prepare them. Herein, we report a new oxidative fluorination reagent capable of stabilizing reactive fluorinated anions. It consists of an SF5−anion and a chemically inert phosphonium cation and is exceptionally thermally stable. Accordingly, it was used to generate the SeF5−and TeF5−anions from the elemental chalcogens and to prepare the unknown tetrafluoro(phenyl)‐λ5‐selenate PhSeF4−and ‐tellurate PhTeF4−from the corresponding diphenyl dichalcogenides. In addition, we show that further derivatization of [PhTeF4]−by oxidation totrans‐PhTeF4O−and subsequent alkylation gives access to a new class oftrans‐(alkoxy)(phenyl)tetrafluoro‐λ6‐tellanes (trans‐PhTeF4OR), thus providing an approach to introduce the functional group into organic molecules.

Diastereoselective Alkylations of Chiral Tetrazolo[1,5-a]azepines via Heterobenzylic Anion Intermediates.

The alkylations of chiral seven-membered rings fused to tetrazoles are highly diastereoselective. The diastereoselectivity depended on the placement and the size of the substituent on the ring and on the electrophile. Subsequent alkylations occurred with high stereoselectivity, allowing for the construction of quaternary stereocenters. Computational studies revealed that torsional effects are responsible for the observed diastereoselectivities. Substituted products can be reduced to the corresponding secondary amines, thus providing an approach for synthesizing diastereomerically enriched azepanes.

Total Synthesis of (+)-Mutilin: A Transannular [2+2] Cycloaddition/Fragmentation Approach.

A new and enantioselective total synthesis of the diterpenoid (+)-mutilin is described. Following a Claisen rearrangement approach to construct the 6,9-bicycle, a transannular [2+2] photocycloaddition and the ensuing ring-opening reaction were implemented to forge the characteristic 5-6-8 propellane-like skeleton. Subsequent late-stage alkylations and reduction completed the synthesis.

A Decade of Germananes: Four Approaches to Their Functionalization.

Since the first synthesis of germanane (GeH) reported in 2013, two-dimensional germanium-based materials have been intensively studied. Over the past decade, several methodologies for the functionalization of germanane have been introduced. The first approach utilized exfoliation of Zintl phase CaGe2 with alkyl halides. Liu's solvothermal method was used for the synthesis of methyl germanane. Another methodology utilized Ge-H activation with sodium naphthalenide and its subsequent alkylation. All of these methods provide functionalized germananes; thus, a comparison of these methods is needed. In this paper, such a comparison of current synthetic approaches towards alkyl germananes is reported, and additionally, a new method for Ge-H activation utilizing a NaK equimolar alloy is presented as a fourth approach. For this purpose, eight alkyl reagents were chosen representing reactive benzyl bromides as well as linear esters and nitriles because they contain easily trackable functional groups. The materials were characterized using Fourier transform infrared spectroscopy, Raman spectroscopy, X-ray photoelectron spectroscopy, and thermogravimetric analysis, and the data were compared. The comparison of all methods revealed not only some drawbacks for each method but also their advantages. The method utilizing sodium naphthalenide provided the lowest degree of surface coverage, whereas the solvothermal method seemed to provide materials with the highest degree of functionalization; unfortunately, the functionalization was also accompanied by a high degree of surface oxidation, i.e., (Ge-OH/Ge═O) formation. The highest degree of surface coverage accompanied by the lowest degree of surface oxidation was achieved employing Goldberger's phase transfer direct exfoliation of CaGe2 as well as Ge-H activation using the NaK alloy with subsequent alkylation.

Production of ethylbenzene and propylbenzene from benzene alkylation using carbon dioxide

Conversion of carbon dioxide (CO 2 ) to aromatics is a promising means of consumption of CO 2 and assists the goal of carbon neutrality. In this issue of Chem Catalysis , Yuan and co-workers report the synthesis of ethylbenzene and propylbenzene from CO 2 by precise control of C–C coupling and subsequent alkylation. Conversion of carbon dioxide (CO 2 ) to aromatics is a promising means of consumption of CO 2 and assists the goal of carbon neutrality. In this issue of Chem Catalysis , Yuan and co-workers report the synthesis of ethylbenzene and propylbenzene from CO 2 by precise control of C–C coupling and subsequent alkylation.

Enhancing the Intermolecular Interactions of Ladder-Type Heteroheptacene-Based Nonfullerene Acceptors for Efficient Polymer Solar Cells by Incorporating Asymmetric Side Chains

Enhancing the Intermolecular Interactions of Ladder-Type Heteroheptacene-Based Nonfullerene Acceptors for Efficient Polymer Solar Cells by Incorporating Asymmetric Side Chains