Rhodium‐Catalyzed Defluorinative Vinylation of gem‐Difluoroalkenes for the Synthesis of 2‐Fluoro‐1,3‐dienes

Herein, we present a strategy for the formation of 2‐fluoro‐1,3‐diene derivatives via rhodium‐catalyzed direct C(sp²)—C(sp²) cross‐coupling of gem‐difluoroalkenes and acrylamides. By merging Rh(III)‐catalyzed C(sp²)–H bond activation and nucleophilic addition/F‐elimination of gem‐difluoroalkene, an efficient defluorinative vinylation reaction is uncovered, which leads to the generation of 2‐fluoro‐1,3‐dienes in moderate to good yields with excellent stereoselectivity under mild conditions. Preliminary mechanistic study suggests unique effects of fluorine substituents which allow the reactivity profile not observed with the congeners bearing heavier halides.     

Rhodium(III)‐Catalyzed Enantioselective Coupling of Indoles and 7‐Azabenzonorbornadienes by C−H Activation/Desymmetrization

Chiral rhodium(III) cyclopentadienyl catalysts (Cp^XRh^III) play significant roles in asymmetric arene C?H activation. Rh/Ir‐catalyzed couplings of arenes and strained rings have been well‐studied, but they have been limited to racemic systems. Reported in this work is the Cp^xRh^III/AgSbF₆‐catalyzed enantioselective desymmetrizative C?C coupling of N‐pyrimidylindoles and 7‐azabenzonorbornadienes with high efficiency and enantioselectivity. The role of AgSbF₆ has been established by mechanistic studies. AgSbF₆ enhances the catalytic activity by suppressing the C3?H activation of the indoles, activation which would otherwise lead to catalytically inactive species.     

2,4‐Dinitrophenol‐Catalyzed α‐C(sp3)−H and C(sp)−H Bond Functionalization of Cyclic Amines and Alkynes: Highly Regio‐/Diastereoselective Synthesis of α‐Alkynyl‐3‐Amino‐2‐Oxindoles

A transition‐metal‐ and oxidant‐free DNP (2,4‐dinitrophenol)‐catalyzed atom‐economical regio‐ and diastereoselective synthesis of monofunctionalized α‐alkynyl‐3‐amino‐2‐oxindole derivatives by C?H bond functionalization of cyclic amines and alkynes with indoline‐2,3‐diones has been developed. This cascade event sequentially involves the reductive amination of indoline‐2,3‐dione by imine formation and cross coupling between C(sp³)?H and C(sp)?H of the cyclic amines and alkynes. This reaction offers an efficient and attractive pathway to different types of α‐alkynyl‐3‐amino‐2‐oxindole derivatives in good yields with a wide tolerance of functional groups. The salient feature of this methodology is that it completely suppresses the homocoupling of alkynes. To the best of our knowledge, this is the first example of a DNP‐catalyzed metal‐free direct C(sp³)?H and C(sp)?H bond functionalization providing biologically active α‐alkynyl‐3‐amino‐2‐oxindole scaffolds.     

Cobalt‐Catalyzed C8‐Dienylation of Quinoline‐N‐Oxides

An efficient Cp*Co^III‐catalyzed C8‐dienylation of quinoline‐N‐oxides was achieved by employing allenes bearing leaving groups at the α‐position as the dienylating agents. The reaction proceeds by Co^III‐catalyzed C?H activation of quinoline‐N‐oxides and regioselective migratory insertion of the allene followed by a β‐oxy elimination, leading to overall dienylation. Site‐selective C?H activation was achieved with excellent selectivity under mild reaction conditions, and 30 mol % of a NaF additive was found to be crucial for the efficient dienylation. The methodology features high stereoselectivity, mild reaction conditions, and good functional‐group tolerance. C8‐alkenylation of quinoline‐N‐oxides was achieved in the case of allenes devoid of leaving groups as coupling partners. Furthermore, gram‐scale preparation and preliminary mechanistic experiments were carried out to gain insights into the reaction mechanism.     

Chiral γ‐Lactams by Enantioselective Palladium(0)‐Catalyzed Cyclopropane Functionalizations

Cyclopropanes fused to pyrrolidines are important structural features found in a number of marketed drugs and development candidates. Typically, their synthesis involves the cyclopropanation of a dihydropyrrole precursor. Reported herein is a complementary approach which employs a palladium(0)‐catalyzed C? H functionalization of an achiral cyclopropane to close the pyrrolidine ring in an enantioselective manner. In contrast to aryl–aryl couplings, palladium(0)‐catalyzed C? H functionalizations involving the formation of C(sp³)? C(sp³) bonds of saturated heterocycles are very scarce. The presented strategy yields cyclopropane‐fused γ‐lactams from chloroacetamide substrates. A bulky Taddol phosphonite ligand in combination with adamantane‐1‐carboxylic acid as a cocatalyst provides the γ‐lactams in excellent yields and enantioselectivities.     

Access to β‐Lactams by Enantioselective Palladium(0)‐Catalyzed C(sp3)H Alkylation

β‐Lactams are very important structural motifs because of their broad biological activities as well as their propensity to engage in ring‐opening reactions. Transition‐metal‐catalyzed C? H functionalizations have emerged as strategy enabling yet uncommon highly efficient disconnections. In contrast to the significant progress of Pd⁰‐catalyzed C? H functionalization for aryl–aryl couplings, related reactions involving the formation of saturated C(sp³)? C(sp³) bonds are elusive. Reported here is an asymmetric C? H functionalization approach to β‐lactams using readily accessible chloroacetamide substrates. Important aspects of this transformation are challenging C(sp³)? C(sp³) and strain‐building reductive eliminations to for the four‐membered ring. In general, the β‐lactams are formed in excellent yields and enantioselectivities using a bulky taddol phosphoramidite ligand in combination with adamantyl carboxylic acid as cocatalyst.     

Rhodium(II)‐Catalyzed Annulation of Azavinyl Carbenes Through Ring‐Expansion of 1,3,5‐Trioxane: Rapid Access to Nine‐Membered 1,3,5,7‐Trioxazonines

The rhodium(II)‐catalyzed denitrogenative coupling of N‐alkylsulfonyl 1,2,3‐triazoles with 1,3,5‐trioxane led to nine‐membered‐ringed trioxazonines in moderate‐to‐good yields. 1,3,5‐Trioxane, acting as an oxygen nucleophile, reacted with the α‐aza‐vinylcarbene intermediate, giving rise to ylide formation, which was probably the key step in the reaction. Triazoles that contained aryl substituents with various electronic and steric features on the C4 carbon atom were well‐tolerated. The synthesis of trioxazonine derivatives was achieved through a one‐pot, two‐step procedure from 1‐mesylazide and a terminal alkyne by combining Cu^I‐catalyzed 1,3‐dipolar cycloaddition and rhodium‐catalyzed transformations.     

Copper‐Catalyzed C(sp3)−H/C(sp3)−H Cross‐Dehydrogenative Coupling with Internal Oxidants: Synthesis of 2‐Trifluoromethyl‐Substituted Dihydropyrrol‐2‐ols

The first oxidative C(sp³)−H/C(sp³)−H cross‐dehydrogenative coupling (CDC) reaction promoted by an internal oxidant is reported. This copper‐catalyzed CDC reaction of oxime acetates and trifluoromethyl ketones provides a simple and efficient approach towards 2‐trifluoromethyldihydropyrrol‐2‐ol derivatives in a highly diastereoselective manner by cascade C(sp³)−C(sp³) bond formation and cyclization. These products were further transformed into various significant and useful trifluoromethylated heterocyclic compounds, such as trifluoromethylated furan, thiophene, pyrrole, dihydropyridazine, and pyridazine derivatives. A trifluoromethylated analogue of an Aβ₄₂ lowering agent was also synthesized smoothly. Preliminary mechanistic studies indicated that this reaction involves a copper(I)/copper(III) catalytic cycle with the oxime acetate acting as an internal oxidant.     

Gold‐Catalyzed Fluorination–Hydration: Synthesis of α‐Fluorobenzofuranones from 2‐Alkynylphenol Derivatives

The Au^I‐catalyzed fluorination–hydration of 2‐alkynylphenol derivatives in the presence of Selectfluor [1‐chloromethyl‐4‐fluoro‐1,4‐diazoniabicyclo‐[2.2.2]octane bis(tetrafluoroborate)] has been developed. This method provides straightforward access to α‐fluorobenzofuranones with the construction of C?O, C=O, and C?F bonds in a single step on the basis of an Au^I/Au^III redox catalytic cycle. Several control experiments, including the asymmetric variant of this reaction, were also conducted to gain insight into the reaction mechanism.     

MnI/AgI Relay Catalysis: Traceless Diazo‐Assisted C(sp2)–H/C(sp3)–H Coupling to β‐(Hetero)Aryl/Alkenyl Ketones

An unprecedented Mn^I/Ag^I‐relay‐catalyzed C(sp²)?H/C(sp³)?H coupling of (vinyl)arenes with α‐diazoketones is reported, wherein the diazo group was exploited as a traceless auxiliary for control of regioselectivity. Challenging β‐(hetero)aryl/alkenyl ketones were obtained through this operationally simple approach. The cascade process merges denitrogenation, carbene rearrangement, C?H activation, and hydroarylation/hydroalkenylation. The robustness of this method was demonstrated at preparative scale and applied to late‐stage diversification of natural products.     

Rhodium(III)‐Catalyzed Intramolecular Redox‐Neutral Annulation of Tethered Alkynes: Formal Total Synthesis of (±)‐Goniomitine

A Rh^III‐catalyzed intramolecular redox‐neutral atom‐economic annulation of a tethered alkyne has been developed to efficiently construct 2‐amidealkyl indoles with completely reversed regioselectivity by a C?H activation pathway. Furthermore, using the Rh^III‐catalyzed C?H activation/annulation as a key step, a one‐pot synthesis of pyrido[1,2‐a]indoles has also been developed and applied to a highly efficient formal total synthesis of (±)‐goniomitine.     

Magnetic Nanoparticle Supported Ionic Liquid Assisted Green Synthesis of Pyrazolopyranopyrimidines and 1,6‐diamino‐2‐oxo‐1,2,3,4‐tetrahydropyridine‐3,5‐ dicarbonitriles

A simple and eco‐friendly green protocol was used for synthesis of pyrazolopyranopyrimidines via four‐component reaction of hydrazine hydrate, ethyl acetoacetate, barbituric acid or dimethyl barbituric acid, and aromatic aldehydes under thermal and solvent‐free conditions in the presence of magnetic nanoparticle supported silica bonded n‐propyl‐4‐aza‐1‐azoniabicyclo[2.2.2]octane chloride (MNPs@DABCO⁺Cl^?) as an efficient, recyclable heterogeneous catalyst. MNPs@DABCO⁺Cl^? also catalyzed the synthesis of 1,6‐diamino‐2‐oxo‐1,2,3,4‐tetrahydropyridine‐3,5‐dicarbonitrile derivatives by four‐component reaction of hydrazine hydrate, malononitrile, ethyl cyanoacetate and ketones under thermal and solvent‐free conditions at 80 °C. These methods are practical and offer many advantages, such as high yields, short reaction times, and simple work‐up.     

Thioamide‐Directed Cobalt(III)‐Catalyzed Selective Amidation of C(sp3)−H Bonds

A mild, oxidant‐free, and selective Cp*Co^III‐catalyzed amidation of thioamides with robust dioxazolone amidating agents via C(sp³)−H bond activation to generate the desired amidated products is reported. The method is efficient and allows for the C−H amidation of a wide range of functionalized thioamides with aryl‐, heteroaryl‐, and alkyl‐substituted dioxazolones under the Cp*Co^III‐catalyzed conditions. The observed regioselectivity towards primary C(sp³)−H activation is supported by computational studies and the cyclometalation is proposed to proceed by means of an external carboxylate‐assisted concerted metalation/deprotonation mechanism. The reported method is a rare example of the use of a directing group other than the commonly used pyridine and quinolone classes for Cp*Co^III‐catalyzed C(sp³)−H functionalization and the first to exploit thioamides.     

Iodine‐Catalyzed Synthesis of Spiro[1,3,4‐benzotriazepine‐2,3′‐indole]‐2′,5(1H,1′H)‐diones under Mild Conditions

The I₂‐catalyzed preparation of spiro[1,3,4‐benzotriazepine‐2,3′‐indole]‐2′,5(1H,1′H)‐diones from 2‐aminobenzohydrazide and isatins in MeCN at room temperature in good‐to‐excellent yields is described. The structure of 3 was corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS data). A plausible mechanism for this type of reaction is proposed (Scheme 2).     

Selective Functionalization of Aromatic C(sp2)−H Bonds in the Presence of Benzylic C(sp3)−H Bonds by Electron‐Deficient Carbenoids Generated from 4‐Acyl‐1‐Sulfonyl‐1,2,3‐Triazoles

A rhodium(II)‐catalyzed reaction of newly prepared 4‐acyl‐1‐sulfonyl‐1,2,3‐triazoles with benzene, and its derivatives, is investigated. Acceptor/acceptor carbenoids generated from 4‐acyltriazoles undergo selective insertion at aromatic C(sp²)−H bonds in the presence of benzylic C(sp³)−H bonds to produce N ‐sulfonylenaminones.     

Catalytic C−H Borylation Using Iron Complexes Bearing 4,5,6,7‐Tetrahydroisoindol‐2‐ide‐Based PNP‐Type Pincer Ligand

Catalytic C?H borylation has been reported using newly designed iron complexes bearing a 4,5,6,7‐tetrahydroisoindol‐2‐ide‐based PNP pincer ligand. The reaction tolerated various five‐membered heteroarenes, such as pyrrole derivatives, as well as six‐membered aromatic compounds, such as toluene. Successful examples of the iron‐catalyzed sp³ C?H borylation of anisole derivatives were also presented.     

“Design” of Boron‐Based Compounds as Pro‐Nucleophiles and Co‐Catalysts for Indium(I)‐Catalyzed Allyl Transfer to Various Csp3‐Type Electrophiles

We have recently uncovered a general indium(I)‐catalyzed method for allylations and propargylation of acetals and ketals with a water‐ and air‐stable allyl boronate. By using a more reactive allyl borane, we have successfully extended this methodology to the more challenging C C coupling with ethers. Herein, we report an improved methodology for the indium(I)‐catalyzed allylation of acetals and ethers, through combination of the allyl boronate with a commercially available “hard” Lewis acid, B‐methoxy‐9‐BBN (BBN=borabicyclo[3.3.1]nonane), as an effective co‐catalyst. Significantly, our work highlights for the first time the correlation between the Lewis acidity of “electrophilic” boron‐based compounds and their “nucleophilic” reactivity in Csp³–Csp³ couplings, catalyzed by a “soft” low‐oxidation main group metal. In addition, we also report several applications of these methodologies to the selective synthesis of various carbohydrate derivatives.     

First Synthesis of （＋）-2,14-Deoxyalatol from α-Santonin

A novel and general approach for synthesis of the multi-oxygenated dihydrofuran sesquiterpenes has been developed starting from santonin. The key steps involve: the strategic acid-catalyzed double-bond shifting affording 4, the novel base-promoted epoxide rearrangement of 5 generating two key functionals (the C5-OH and the Δ^7,11 double bond), and the stereoselective cyclization of tetrahydrofuran ring without pre-controlling the stereochemistry of C-7. As an example of this approach, synthesis of ( )-2,14-deoxyalatol was described in detail.     

Ring‐Opening and polymerization of 1‐[2′‐(heptaphenylcyclotetrasiloxanyl)ethyl]‐1,3,3,5,5‐pentamethylcyclotrisiloxane

1‐[2′‐(Heptaphenylcyclotetrasiloxanyl)ethyl]‐1,3,3,5,5‐pentamethylcyclotetrasiloxane ( II ) was prepared from 1‐[2′‐(methyldichlorosilyl)ethyl]‐1,3,3,5,5,7,7‐heptaphenylcyclotetrasiloxane ( I ) and tetramethyldisiloxane‐1,3‐diol. Acid‐catalyzed ring‐opening of II in the presence of tetramethyldisiloxane gave 1,9‐dihydrido‐5‐[2′‐(heptaphenylcyclotetrasiloxanyl)ethyl]nonamethylpentasiloxane ( III ) and 1,9‐dihydrido‐3‐[2′‐(heptaphenylcyclotetrasiloxanyl)ethyl]nonamethylpentasiloxane ( IV ). Both acid‐ and base‐catalyzed ring‐opening polymerization of II gives highly viscous, transparent polymers. The structures of I – IV and polymers were determined by UV, IR, ¹H, ¹³C, and ²⁹Si NMR spectroscopy. In addition, molecular weights obtained by GPC and NMR end group analysis were confirmed with mass spectrometry. On the basis of ²⁹Si NMR spectroscopy, the polymers appear to result exclusively from ring‐opening of the cyclotrisiloxane ring. No evidence for ring‐opening of the cyclotetrasiloxane ring was observed. Polymer properties were determined by DSC and TGA. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 137–146, 2006     

Efficient Synthesis of Pyrrolo[2,1‐a]isoquinoline and Pyrrolo[1,2‐a]quinoline Derivatives via One‐pot Two‐step Metal‐catalyzed Three‐component Reactions

A sequential one‐pot two‐step reaction for efficient synthesis of pyrrolo[2,1‐a]isoquinoline and pyrrolo[1,2‐a]quinoline derivatives in good yields has been successfully developed. The reaction included firstly Cu‐catalyzed three‐component reaction of isoquinoline (quinoline), acetylenedicarboxylate and alkynylbenzene and then Pd‐catalyzed intramolecular C(sp)‐C(sp²) coupling reaction of initially formed 1‐alkenyl‐2‐alkynyl‐1,2‐dihydroisoquinoline (1,2‐dihydroquinoline).