Bond Formation Sequence Research Articles

Rh(III)‐Catalyzed Cascade Cyclization of 2‐Aryl‐3H‐indoles and CF3‐Imidoyl Sulfoxonium Ylides Toward Trifluoroacetimidoyl‐Substituted 11H‐Isoindolo[2,1‐a]indoles

AbstractA rhodium(III)‐catalyzed C−H activation/[4+1] annulation of 2‐aryl‐3H‐indoles and CF3‐substituted imidoyl sulfoxonium ylides (TFISYs) has been achieved, producing a wide variety of trifluoroacetimidoyl‐substituted 11H‐isoindolo[2,1‐a]indoles in 51–86% yields. The cascade reaction involves C−H imidoylmethylation, tautomerization and AgOAc‐mediated C−N bond formation sequence. The reaction could be scaled up to 2 mmol scale.

Adventures in Total Synthesis – The Next Chapter

AbstractThis account summarizes the author’s endeavors in target-oriented synthesis at Seoul National University since 2011. A collection of the most celebrated molecules in total synthesis are revisited and the author’s solutions to these historical challenges are presented. In particular, the unique perception of their molecular frameworks and unprecedented bond-forming sequences form the basis of the newly developed strategies. Together with a ‘personal touch’ on these selected stories, the author hopes that this account will offer new insights and fresh perspectives for all levels of enthusiasts of target-oriented total synthesis.1 Introduction2.1 Synthesis of Strychnine2.2 Synthesis of Actinophyllic Acid2.3 Synthesis of Dendrobine2.4 Synthesis of Communesin2.5 Synthesis of Morphinans2.6 Synthesis of Reserpine2.7 Synthesis of Quinine and Quinidine2.8 Synthesis of Haouamine2.9 Future Work3 Summary and Outlook4 Abbreviations

Synthesis of quinazolinones via Cp*Co(III)-catalyzed C-H functionalization of primary amides with oxadiazolones.

Multi-heteroatom heterocycle synthesis through direct C-H bond activation is methodologically appealing but synthetically challenging. An efficient double C-N bond formation sequence to prepare quinazolinones utilizing primary amides and oxadiazolones in a catalytic redox-neutral [CoCp*(CO)I2]/AgSbF6 system, where oxadiazolone could function as an internal oxidant to maintain the catalytic cycle, is reported. Amide-directed C-H bond activation and oxadiazolone decarboxylation are key to the success of this traceless, atom- and step-economic, and cascade approach for the construction of the quinazolinone skeleton.

Copper‐Catalyzed Decarbonylative Cyclization of Isatins and Trifluoroacetimidohydrazides for the Synthesis of 2‐(5‐Trifluoromethyl‐1,2,4‐triazol‐3‐yl)anilines

AbstractA copper‐catalyzed intramolecular decarbonylative cyclization reaction of isatins and trifluoroacetimidohydrazides for the synthesis of 2‐(5‐trifluoromethyl‐1,2,4‐triazol‐3‐yl)aniline derivatives has been developed. This transformation proceeds through a cascade condensation, hydrolysis, decarboxylation, and intramolecular C−N bond formation sequence. The obtained 1,2,4‐triazole products bearing a free amino group can be readily converted into other useful compounds.magnified image

Unveiling the synthesis of spirocyclic, tricyclic, and bicyclic triazolooxazines from intramolecular [3 + 2] azide-alkyne cycloadditions with a molecular electron density theory perspective

The intramolecular [3+2] cycloaddition (32CA) reactions of azido alkynes leading to spirocyclic, tricyclic, and bicyclic triazolooxazines has been studied within the molecular electron density theory (MEDT) at the MPWB1K/6-311G(d,p) level. The electron localization function (ELF) characterizes the azido alkynes as zwitterionic species. Analysis of the conceptual DFT indices allows classifying the azide moiety as the electrophilic counterpart and the alkyne as the nucleophilic one. These 32CA reactions are under kinetic control with the activation free energies of 23.4–26.7 kcal mol−1. Along the reaction path, the pseudoradical centre is created initially at C4, consistent with the Parr function analysis; however, the sequence of bond formation is controlled by the energetically feasible formation of the six-membered oxazine ring. The intermolecular interactions at the transition states were characterized from the quantum theory of atoms in molecules (QTAIM) study and the non-covalent interaction (NCI) gradient isosurfaces.

Functionalization of 9-thioxanthone at the 1-position: From arylamino derivatives to [1]benzo(thio)pyrano[4,3,2-de]benzothieno[2,3-b]quinolines of biological interest.

Original 1-amino substituted thioxanthone derivatives were easily prepared from the bare heterocycle by a deprotometalation-iodolysis-copper-catalyzed CN bond formation sequence. This last reaction delivered mono- or/and diarylated products depending on the aniline involved. 1-Amino-9-thioxanthone was also prepared and reacted with 2-iodoheterocycles. Interestingly, while 1-(arylamino)-9-thioxanthones could be isolated, their subsequent cyclization was found to deliver original hexacyclic derivatives of helicoidal nature. Evaluation of their photophysical properties revealed high fluorescence in polar media, indicating potential applications for biological imaging. These compounds being able to inhibit PIM1 kinase, their putative binding mode was examined through molecular modeling experiments. Altogether, these results tend to suggest the discovery of a new family of fluorescent PIM inhibitors and pave the way for their future rational optimization.

Diastereoselective Palladium-Catalyzed (3 + 2)-Cycloadditions from Cyclic Imines and Vinyl Aziridines.

The synthesis of cyclic imidazolidines via two N-C bond-forming sequences has been developed. The transformation goes through a (3 + 2)-cycloaddition reaction in the presence of catalytic amounts of palladium by combining several vinyl aziridines and cyclic N-sulfonyl imines. Interestingly, the use of LiCl as additive allowed the improvement of diastereoselectivities when less encumbered substrates were used. The imidazolidine derivatives that bear aminal cores are isolated in high yields (15 examples, up to 96% yield) and diastereoselectivities (up to >20:1).

Interconversion of Molybdenum Imido and Amido Complexes by Proton-Coupled Electron Transfer.

Interconversion of the molybdenum amido [(Ph Tpy)(PPh2 Me)2 Mo(NHtBuAr)][BArF24 ] (Ph Tpy=4'-Ph-2,2',6',2"-terpyridine; tBuAr=4-tert-butyl-C6 H4 ; ArF24 =(C6 H3 -3,5-(CF3 )2 )4 ) and imido [(Ph Tpy)(PPh2 Me)2 Mo(NtBuAr)][BArF24 ] complexes has been accomplished by proton-coupled electron transfer. The 2,4,6-tri-tert-butylphenoxyl radical was used as an oxidant and the non-classical ammine complex [(Ph Tpy)(PPh2 Me)2 Mo(NH3 )][BArF24 ] as the reductant. The N-H bond dissociation free energy (BDFE) of the amido N-H bond formed and cleaved in the sequence was experimentally bracketed between 45.8 and 52.3 kcal mol-1 , in agreement with a DFT-computed value of 48 kcal mol-1 . The N-H BDFE in combination with electrochemical data eliminate proton transfer as the first step in the N-H bond-forming sequence and favor initial electron transfer or concerted pathways.

Development of a One-Pot Four C-C Bond-Forming Sequence Based on Palladium/Ruthenium Tandem Catalysis.

A one-pot four C-C bond-forming sequence has been developed using two distinct transition metal complexes. The sequence entails a double Pd-catalyzed allylic alkylation followed by a Ru-catalyzed ring-closing metathesis and a Pd-catalyzed Heck coupling. The use of various active methylene nucleophiles was examined with yields up to 76% (93% per C-C bond).

Spiro-Fused Perylene Diimide Arrays.

The straightforward palladium-catalyzed synthesis protocol toward spiro-fused perylene diimides is developed. The reaction involves two palladium-catalyzed C-H activations and 4-fold C-C bond formation sequence from readily available precursors. This facile and step-economic approach also provides another convenient access to ethylene-bridged dimer (NDP) and further π-extended spiro system (SNTP). In addition, the molecular structure of spirodiperylenetetraimide (SDP) is illustrated to show a three-dimensional (3D) cruciform configuration, and its absorbance is distinctly red-shifted due to the significant spiroconjugation effect. With combined properties of broadened and intensive absorption, aligned LUMO levels, and unique molecular geometry, the spiro-fused PDI system represents a new kind of high-performance semiconducting framework as the electron acceptor in high-efficiency organic solar cells.

C-H Bond Trifluoromethylation of Arenes Enabled by a Robust, High-Valent Nickel(IV) Complex.

The robust, high-valent NiIV complex [(Py)2 NiIV F2 (CF3 )2 ] (Py=pyridine) was synthesized and fully characterized by NMR spectroscopy, X-ray diffraction, and elemental analysis. It reacts with aromatic compounds at 25 °C to form the corresponding benzotrifluorides in nearly quantitative yield. The monomeric and dimeric NiIII CF3 complexes 2⋅Py and 2 were identified as key intermediates, and their structures were unambiguously determined by EPR spectroscopy and X-ray diffraction. Preliminary kinetic studies in combination with the isolation of reaction intermediates confirmed that the C-H bond-breaking/C-CF3 bond-forming sequence can occur both at NiIV CF3 and NiIII CF3 centers.

Pd-catalyzed Auto-Tandem Cascades Based on N-Sulfonylhydrazones: Hetero- and Carbocyclization Processes

The Pd-catalyzed cross-coupling between N-tosylhydrazones and organic halides is a powerful method for the creation of C–C bonds. This transformation has been included recently in cascade processes in which the same catalyst promotes various independent catalytic steps, a process known as auto-tandem catalysis. This strategy proves to be very useful for the construction of relatively complex carbo- and heterocyclic structures, as well as for the generation of molecular diversity. This short review will cover the different Pd-catalyzed auto-tandem reactions­ involving N-tosylhydrazones organized by the bond-forming sequence: C–C/C–N and C–C/C–C. Some examples of related tandem reactions leading to acyclic compounds are also highlighted.1 Introduction2 Auto-Tandem C–C/C–N Bond-Forming Reactions3 Auto-Tandem C–C/C–C Bond-Forming Reactions4 Tandem Reactions for the Synthesis of Linear Molecules5 Summary and Outlook

A Concise, Efficient and Scalable Total Synthesis of Thapsigargin and Nortrilobolide from (R)-(-)-Carvone.

A concise, efficient and scalable synthesis of thapsigargin and nortrilobolide from commercially available (R)-(-)-carvone was developed. Our synthetic strategy is inspired by nature's carbon-carbon bond formation sequence, which facilitates the construction of a highly functionalized sesquiterpene lactone skeleton in five steps via an enantioselective ketone alkylation and a diastereoselective pinacol cyclization. We envision that this strategy will permit the construction of other members of the family, structural analogs and provide a practical synthetic route to these important bioactive agents. In addition, we anticipate that the prodrug Mipsagargin, which is currently in late-stage clinical trials for the treatment of cancer, will also be accessible via this strategy. Hence, the limited availability from natural sources, coupled with an estimated demand of one metric ton per annum for the prodrug, provides a compelling mandate to develop practical total syntheses of these agents.

Copper-Catalyzed Double C–N Bond Formation for the Synthesis of Diverse Benzimidazoles from N-Alkyl-2-iodoaniline and Sodium Azide

An efficient approach to the synthesis of benzimidazole derivatives has been achieved by copper-catalyzed double C–N bonds formation of N-alkyl-2-iodoaniline and sodium azide. The reaction was supposed to proceed through copper-catalyzed tandem reaction of SNAr reaction, aerobic oxidation of C(sp3)–H bond and intramolecular C–N bond formation sequence. Structurally diverse 2-aryl, alkenyl and alkyl benzoimidazole derivatives were assembled by this methodology.

Synthesis of Fluorenes Starting from 2-Iodobiphenyls and CH2Br2 through Palladium-Catalyzed Dual C-C Bond Formation.

A facile and efficient approach is developed for the synthesis of fluorene and its derivatives starting from 2-iodobiphenyls and CH2Br2. A range of fluorene derivatives can be synthesized under relatively mild conditions. The reaction proceeds via a tandem palladium-catalyzed dual C-C bond formation sequence through the key dibenzopalladacyclopentadiene intermediates, which are obtained from 2-iodobiphenyls through palladium-catalyzed C-H activation.

Quinazoline Synthesis via Rh(III)-Catalyzed Intermolecular C-H Functionalization of Benzimidates with Dioxazolones.

An efficient double C-N bond formation sequence to prepare highly substituted quinazolines utilizing benzimidates and dioxazolones under the catalytic redox-neutral [Cp*RhCl2]2/AgBF4 system, where dioxazolones could work as an internal oxidant to maintain the catalytic cycle, is reported. N-Unsubstituted imine not only acts as a directing group but also functions as a nucleophile in postcoupling cyclization, and dioxazolone acts as a coupling partner for access to heterocycle.

Electrode instead of catalyst and enzyme. A greener protocol for the synthesis of new 2-hydroxyacetamide derivatives containing a γ-lactone ring

Electrochemical synthesis of novel 2-hydroxyacetamides was performed in a one-pot protocol including the oxygen activation, extradiol cleavage, lactonization and amide bond formation sequence without any catalyst and enzyme.

ChemInform Abstract: Synthesis of Quinolines by Visible‐Light Induced Radical Reaction of Vinyl Azides and α‐Carbonyl Benzyl Bromides.

AbstractVisible‐light‐induced radical reaction of vinyl azides and α‐carbonyl benzyl bromides provides an efficient route to polysubstituted quinolines via a C—C and C—N bond formation sequence.

Silver(I)-catalyzed annulation for the regioselective synthesis of N-imino-γ-carbolinium ylides from hydrazones of indole-3-carbonyl derivatives and propargylic alcohols.

A regioselective efficient synthetic approach to N-imino-γ-carbolinium ylides via AgOTf-catalyzed iminoannulation has been developed. This transformation proceeds via a silver(i) triflate-catalyzed consecutive Friedel-Crafts reaction/N-C bond formation sequence between the readily available indole derivatives and propargylic alcohols.

A gold-catalysed fully intermolecular oxidation and sulfur-ylide formation sequence on ynamides.

An efficient C-O, C-S and C-C bond-forming sequence leads to functionalised compounds bearing sulfur-substituted quaternary carbons. Ynamides are employed as diazo-equivalents to access the [2,3]-sigmatropic rearrangements of allyl sulfonium ylides by a three-component chemoselective oxidation and intermolecular ylide formation.