Intramolecular Cross-coupling Research Articles

Cr-Catalyzed Intramolecular Arylative Cross-Coupling of Unactivated C-H Bonds with C-Halide Bonds.

We report here a chromium-catalyzed intramolecular arylation of unactivated C-H bonds with C-halide bonds under mild conditions. This reaction was enabled by using a low-cost CrCl2 salt as the precatalyst in combination with allylmagnesium bromide and E/Z-mixed 1-halo-2-styrylarenes as substates, providing a strategy for the construction of functionalized phenanthrene compounds without using external ligands.

Nickel-Catalyzed Inter- and Intramolecular Reductive Cross-Coupling Reactions of Arylbenzylammonium Salts through Highly Site-Selective C–N Bond Cleavage

Nickel-Catalyzed Inter- and Intramolecular Reductive Cross-Coupling Reactions of Arylbenzylammonium Salts through Highly Site-Selective C–N Bond Cleavage

Boron‐Copper 1,3‐Rearrangement: the New Concept Behind the Boryl Migration from C(sp2) in Alkenyl Boranes to C(sp3)

AbstractRegioselective borylcupration of borylated skipped (Z)‐dienes generates diborylated alkylcopper species that are involved in an intramolecular stereospecific B/Cu 1,3‐rearrangement by migration of Bpin moiety from C(sp2) to C(sp3). DFT mechanistic studies showed that boryl migration occurs through the formation of 4‐membered boracycle intermediate with a moderate free‐energy barrier. Moreover, the use of KOMe forms stable Lewis base adducts with Bpin moieties that blocks the reaction. Subsequently to the 1,3‐boron shift, the in situ electrophilic trapping allows selective C−H, C−C and C−X bonds, followed by intramolecular cross coupling giving access to cyclic functionalized alkylidenecyclohexanes or alkylidenecyclobutanes.

Boron-Copper 1,3-Rearrangement: the New Concept Behind the Boryl Migration from C(sp2 ) in Alkenyl Boranes to C(sp3 ).

Regioselective borylcupration of borylated skipped (Z)-dienes generates diborylated alkylcopper species that are involved in an intramolecular stereospecific B/Cu 1,3-rearrangement by migration of Bpin moiety from C(sp2 ) to C(sp3 ). DFT mechanistic studies showed that boryl migration occurs through the formation of 4-membered boracycle intermediate with a moderate free-energy barrier. Moreover, the use of KOMe forms stable Lewis base adducts with Bpin moieties that blocks the reaction. Subsequently to the 1,3-boron shift, the in situ electrophilic trapping allows selective C-H, C-C and C-X bonds, followed by intramolecular cross coupling giving access to cyclic functionalized alkylidenecyclohexanes or alkylidenecyclobutanes.

Synthese und Biologische Untersuchungen von C(13)/C(13′)‐Bis(desmethyl)disorazol Z**

AbstractWir beschreiben hier die Totalsynthese des Makrodiolids C(13)/C(13′)‐Bis(desmethyl)disorazol Z über die Bildung des Makrozyklus durch eine doppelte inter‐/intramolekulare Stille‐Kreuzkupplung eines monomeren Vinylstannan/Vinyliodid Vorläufers. Der Schlüsselschritt in der Synthese dieses Vorläufers ist die stereoselektive Aldolreaktion eines formalen Evans Acetat‐Aldolprodukts mit Crotonaldehyd. Wie mitttels Röntgenkristallographie gezeigt werden konnte, ist der Bindungsmodus des C(13)/C(13′)‐Bis(desmethyl)disorazol Z an Tubulin praktisch identisch mit demjenigen des Naturstoffs Disorazol Z. Desgleichen unterdrückt das C(13)/C(13′)‐Bis(desmethyl)disorazol Z die Tubulinpolymerisation zumindest gleich stark wie das Disorazol Z und es hemmt das Zellwachstum offenbar sogar mit höherer Potenz.

Synthesis and Biological Evaluation of C(13)/C(13')-Bis(desmethyl)disorazole Z.

We describe the total synthesis of the macrodiolide C(13)/C(13')-bis(desmethyl)disorazole Z through double inter-/intramolecular Stille cross-coupling of a monomeric vinyl stannane/vinyl iodide precursor to form the macrocycle. The key step in the synthesis of this precursor was a stereoselective aldol reaction of a formal Evans acetate aldol product with crotonaldehyde. As demonstrated by X-ray crystallography, the binding mode of C(13)/C(13')-bis(desmethyl)disorazole Z to tubulin is virtually identical with that of the natural product disorazole Z. Likewise, C(13)/C(13')-bis(desmethyl)disorazole Z inhibits tubulin assembly with at least the same potency as disorazole Z and it appears to be a more potent cell growth inhibitor.

First synthesis of new polycyclic systems from ortho-di(heteroaryl)-substituted furazanopyrazine derivatives by the Scholl reaction

A facile synthetic protocol to hard-to-get polycyclic (hetero)-aromatic compounds annulated to [1,2,4]oxadiazolo[3,4-b]-pyrazine scaffold via the FeCl3-mediated intramolecular Scholl cross-coupling has been developed. Based on the electrochemical and photophysical measurements, the synthesized polycyclic systems may be regarded as narrow band-gap (from 1.42 to 1.89 eV) n-type organic semiconductors whose energy levels are comparable to those of the commercially available n-type semiconductors

Studies toward synthesis of the core skeleton of spiroaspertrione A.

Bioassay-guided isolation of spiroaspertrione A from cultures of Aspergillus sp. TJ23 in 2017 demonstrated potent resensitization of oxacillin against methicillin-resistant Staphylococcus aureus by lowering the oxacillin minimal inhibitory concentration up to 32-fold. To construct this unique spiro[bicyclo[3.2.2]nonane-2,1′-cyclohexane] system, a protocol for ceric ammonium nitrate-induced intramolecular cross-coupling of silyl enolate is disclosed.

Divergent Pd-catalyzed Functionalization of 4-Oxazolin-2-ones and 4-Methylene-2-oxazolidinones and Synthesis of Heterocyclic-Fused Indoles.

Palladium-catalyzed functionalization was presently performed on two building blocks: 4-oxazolin-2-ones and 4-methylene-2-oxazolidinones. Direct Heck arylation of 4-oxazolin-2-ones led to a series of 5-aryl-4-oxazolin-2-ones, including analogues with N-chiral auxiliary, in an almost quantitative yield. The Pd(II)-catalyzed homocoupling reaction of 4-oxazolin-2-ones provided novel heterocyclic across-ring dienes. Meanwhile, the intramolecular cross-coupling of N-aryl-4-methylene-2-oxazolidinones furnished a series of oxazolo[3,4-a]indol-3-ones. Further functionalization of 4-methylene-2-oxazolidinones afforded substituted indoles and heterocyclic-fused indoles with aryl, bromo, carbinol, formyl, and vinyl groups. A computational study was carried out to account for the behavior of the formylated derivatives. The currently developed methodology was applied to a new formal total synthesis of ellipticine.

Desymmetrization of Malononitriles by Intramolecular Nickel-Catalyzed Reductive Cross-Coupling

Key words reductive cross-coupling - malononitriles - nickel catalysis - Phox ligands - desymmetrization - all-carbon quaternary stereocenters

Enantioselective Nickel-Catalyzed Reductive Aryl/Alkenyl-Cyano Cyclization Coupling to All-Carbon Quaternary Stereocenters.

An enantioselective nickel-catalyzed intramolecular reductive cross-coupling of C(sp2) electrophiles and cyano groups is reported. Enantioenriched CN-containing all-carbon quaternary stereocenters are assembled by desymmetrizing cyclization of aryl/alkenyl halide-tethered malononitriles. The use of an organic reductant, (EtO)2MeSiH, is crucial to the enantioselectivity and reactivity. Applications of the method are demonstrated through the synthesis of bioactive molecules and their cyanated analogues and the total synthesis of the natural product diomuscinone. This study exhibits the potential of desymmetrizing reductive coupling strategies to access structurally rigid and synthetically versatile molecules from readily available starting materials.

Formation of the Tertiary Sulfonamide C(sp3)-N Bond Using Alkyl Boronic Ester via Intramolecular and Intermolecular Copper-Catalyzed Oxidative Cross-Coupling.

A synthetic strategy for the formation of C(sp3)-N bonds, particularly through a copper-catalyzed oxidative cross-coupling, is rare. Herein, we report a novel synthetic approach for the preparation of tertiary sulfonamides via copper-catalyzed intra- and intermolecular oxidative C(sp3)-N cross-coupling reactions. This method allows the utilization of the readily available C(sp3)-based pinacol boronate as a substrate and the tolerance of a wide range of functional groups under mild reaction conditions. The success of this strategy relies on the unprecedented additive effects of silanol and NaIO4.

Transition-Metal-Free Reductive Cross-Coupling Employing Metabisulfite as a Connector: General Construction of Alkyl–Alkyl Sulfones

Transition-Metal-Free Reductive Cross-Coupling Employing Metabisulfite as a Connector: General Construction of Alkyl–Alkyl Sulfones

Electrochemical Synthesis of Fused Indole Alkaloids By Controlling Radical Cation Reactivities

Pyrrolophenanthridone alkaloids are isolated from Amaryllidaceae and it has fused N-benzoyl indole as core structure. Many researchers targeted this simple alkaloids to demonstrate various synthetic method1), such as palladium- or hypervalent iodine-mediated intramolecular cross-coupling, tetrazine-promoted inverse electron-demand Diels-Alder reaction. All examples required DDQ oxidation to convert indoline to indole.We established metal- and oxidant-free electrochemical intramolecular C(sp2)-H cross-coupling and indole synthesis reaction. These reactions were initiated by same anodic oxidation for electron-rich indoline ring, but different electron-transfer pathway was occurred in both cyclization and indole forming reaction. Moreover, non-coordinative medium has crucial role to control reactivity of radical cation. Increasing electrophilicity of radical cation is key strategy to accomplish intramolecular cross-coupling. MeNO2-LiClO4 and HFIP (1,1,1,3,3,3,-hexafluoro-2-propanol), which known as suitable medium for radical cation-mediated reaction2), had not worked well for this reaction. However, MeNO2-HFIP (9:1) mixed solvent strongly enhanced the reactivity of radical cations. This phenomenon was occurred by synergetic stabilization effect of MeNO2 and HFIP3). The low donor number of MeNO2 and anion trapping ability of HFIP made non-coordinative environment and resulting electrophilic radical cation was maintained in this medium. Dehydrogenative indole forming reaction was accomplished in Lewis-basic condition (MeCN-Bu4NClO4), and collidine additive enhanced benzylic deprotonation from radical cation.Finally, we applied both reactions for the synthesis of seven naturally occurred pyrrolophenanthridone alkaloids4). References (1) (a) Black, DC.; Keller, PA.; Kumar, N. Tetrahedron Lett. 1989, 30, 5807-5808; (b) Ganton, MD.; Kerr, MA. Org. Lett. 2005, 21, 4777-4779; (c) Boger, DL.; Wolkenberg, SE. J. Org. Chem. 2000, 65, 9120-9124.(2) (a) Okada, Y.; Chiba, K. Chem. Rev. 2018, 118, 4592-4630; (b) Kirste, A.; Nieger, M.; Malkowsky, IM.; Stecker, F.; Fisher, A.; Waldvogel, SR. Chem. Eur. J. 2009, 15, 2273-2277.(3) (a) Shida, N.; Imada, Y.; Nagahara, S.; Okada, Y.; Chiba, K. Commun. Chem. 2019, 2, 24; (b) Shida, N.; Imada, Y.; Okada, Y.; Chiba, K. Eur. J. Org. Chem. 2020, 2020, 570-574.(4) Okamoto, K.; Chiba, K. Org. Lett. 2020, accepted (DOI: 10.1021/acs.orglett.0c01082). Figure 1

I2/KI-Catalyzed synthesis of 5-trifluoromethylated 1,2,4,6-tetrazepine-3-thiones by annulation of trifluoroacetimidoyl chlorides and thiosemicarbazones

An efficient and simple protocol for the synthesis of trifluoromethylated 1,2,4,6-tetrazepines by intramolecular cross-coupling of C(sp2)–H and N–H bonds using I2/KI catalyst under aerobic oxidative has been demonstrated. This research exhibited a nucleophilic substitution reaction and then oxidative cyclization between trifluoroacetimidoyl chlorides and thiosemicarbazones.

Synthetic Studies towards the Total Synthesis of Indole Alkaloids Containing Indolyl Lactam Frameworks

AbstractIn this account, recent progress on the synthetic studies of several monoterpene indole alkaloids, (±)-mersicarpine, misassigned (±)-tronoharine, and (±)-leuconodines D and E, is summarized. Specifically, the rationale for the design and development of the Lewis acid catalyzed SN1-type substitution and formal [3+3] cycloaddition reaction of indol-2-yl carbinols, and the Pd-catalyzed aerobic oxidative intramolecular Heck cross-coupling of indolyl amides tethered with a terminal olefin functionality, are emphasized. These key reactions set the basis for the rapid construction of the fused ring skeleton containing an all-carbon quaternary center at the indol-2-yl position.1 Introduction2 Synthetic Study of (±)-Mersicarpine3 Synthetic Study of the Misassigned (±)-Tronoharine4 Study of the Asymmetric Reaction of Indol-2-yl Carbinols5 Synthetic Study of (±)-Leuconodines D and E6 Conclusion

Electrochemical Total Synthesis of Pratosine By Controlling for the Anodically Initiated One-/Two-Electron Transfer Process

Pratosine is a type of a pyrrolophenanthridone alkaloid that includes indole ring and electron donating group-substituted N-benzoyl moiety. Many researchers demonstrated various synthetic reactions to access a simple poly-heterocyclic structure of pyrrolophenanthridone. For instance, intramolecular cyclization between indoline and N-benzoyl moiety was accomplished by stoichiometric Pd-mediated C-H activation1, hypervalent iodine mediated oxidative cross-coupling2 and inverse electron-demand Diels-Alder reaction3. Continuously DDQ oxidation to convert indoline to indole is necessary in all case. We established electrochemical intramolecular radical cation cross-coupling and indole synthesis reaction. These reaction was initiated by same anodic oxidation for electron-rich benzoyl group, but acid or base additive-dependent different electron-transfer pathway was occurred in both cyclization and indole ring forming reaction.Reference(1) DC. Black, PA. Keller, N. Kumar, Tetrahedron Lett. 1989, 30, 5807-5808.(2) MD. Ganton, MA. Kerr, Org. Lett. 2005, 7, 4777-4779.(3) DL. Boger, SE. Wolkenberg, J. Org. Chem. 2000, 65, 9120-9124. Figure 1

Electrochemical Total Synthesis of Pyrrolophenanthridone Alkaloids: Controlling the Anodically Initiated Electron Transfer Process.

Electrochemical intramolecular C(sp2)-H cross-coupling and dehydrogenative indole synthesis were developed. Both reactions were initiated by anodic oxidation of the same electron-rich indoline moiety, but the product selectivity was controlled by different electron-transfer processes. Intramolecular cross-coupling was achieved by the generation of a strong electrophilic radical cation intermediate in the MeNO2-HFIP-LiClO4 system. Indole formation was accomplished through benzylic oxidation and continuous deprotonation. We applied these reactions to the total synthesis of natural pyrrolophenanthridone alkaloids.

5-Iodo-1H-1,2,3-triazoles as Versatile Building Blocks

Copper-catalyzed azide–alkyne cycloaddition is a useful tool for the synthesis of both 1,2,3-triazoles and 5-iodo-1H-1,2,3-triazoles starting from either terminal alkynes or iodoalkynes. 5-Iodotriazoles have been recognized as very useful building blocks for the synthesis of diverse 1,4,5-trisubstituted 1,2,3-triazoles. Synthetic application of 5-iodo-1,2,3-triazoles through the creation of a new C–C, C–heteroatom, or C–D(T) bond along with the application areas of both iodotriazoles and products of their modification including radiolabeled compounds are discussed.1 Introduction2 Synthetic Approaches to 5-Iodo-1H-1,2,3-triazoles3 5-Iodotriazoles in C–C Bond Formation3.1 Intermolecular C–C Cross-Coupling3.2 Intramolecular Cross-Coupling: Direct Arylation and C–I/C–I Homocoupling­3.3 Other Transformations4 5-Iodotriazoles in Radiolabeling, Halogen Exchange, and Heterocoupling Reactions5 Summary

Multicomponent Reductive Cross-Coupling of an Inorganic Sulfur Dioxide Surrogate: Straightforward Construction of Diversely Functionalized Sulfones.

Conventionally, sulfones are prepared by oxidation of sulfides with strong oxidants. Now, a multicomponent reductive cross-coupling involving an inorganic salt (sodium metabisulfite) for the straightforward construction of sulfones is disclosed. Both intramolecular and intermolecular reductive cross-couplings were comprehensively explored, and diverse sulfones were accessible from the corresponding alkyl and aryl halides. Intramolecular cyclic sulfones were systematically obtained from five- to twelve-membered rings. Naturally occurring aliphatic systems, such as steroids, saccharides, and amino acids, were highly compatible with the SO2 -insertion reductive cross-coupling. Four clinically applied drug molecules, which include multiple heteroatoms and functional groups with active hydrogens, were successfully prepared via a late-stage SO2 insertion. Mechanistic studies show that alkyl radicals and sulfonyl radicals were both involved as intermediates in this transformation.