Assembly of Pyrano[2,3-c]pyrazol-5-ol from Electron-Deficient Bifunctional Peroxides via Michael Addition/Cyclization/Ring-Opening.

Metal-catalyzed C─H and C─C functionalizations have become an increasingly viable approach, which allows the direct formation of C─C and C─heteroatom bonds in an atom- and step-economical manner. However, the significant accomplishments in this field have heavily relied on the use of precious transition metals, such as rhodium, palladium, ruthenium, and iridium, over the last few decades. The high cost and potential toxicity of these metals limit the applications in pharmaceutical and fine chemical industries. Therefore, developing efficient and economic C─H and C─C functionalization by inexpensive and Earth-abundant metals is highly desirable. In this thesis, we summarize our recent achievements in direct C─H and C─C bond transformations by cobalt(III)- and manganese(I)-catalysis. In the first project, a cobalt(III)-catalyzed C─H/N─O functionalization was achieved for the synthesis of substituted isoquinolines derivatives. Notable features of this developed annulation reaction were a wide substrate scope applicable and tolerance of various functional groups, affording the isoquinolines in good yields with high regio-selectivities. The mechanistic findings, including H/D exchange, competition experiments and KIE studies, revealed a reversible and facile BIES-type C─H metalation pathway was involved. In the second project, a good site- and regio-selective cobalt(III)-catalyzed C─H annulation of various nitrones approached the novel and useful indole synthesis. The versatile cobalt(III) catalyst proved to be particularly effective for challenging unsymmetrically substituted alkynes, when employing a catalytic amounts of Piv-Leu-OH as ligand, delivering unprotected indoles in good yields with excellent levels of regioselectivity. In the third project, we developed the first cobalt(III)-catalyzed position-selective C─H functionalization, which fully tolerated strongly coordinating heterocycles, such as pyridines, pyrimidines, and pyrazoles. The preliminary mechanistic studies, especially the H/D exchange experiments, indicated that the positional selectivity of the reaction is determined in the C─N bond forming step. In the fourth project, a cobalt(III)-catalyzed domino C─H/N─H allylation reaction of aryl imidates with dioxolanones was accomplished. The reaction was performed under mild reaction conditions with water and generated CO2 as the only byproducts. Aryl-substituted imidates bearing various electron-donating and electron-withdrawing groups are compatible with the reaction conditions, delivering the cyclization products in good yields with high levels of regio-selectivity. In the fifth project, a manganese(I)-catalyzed decarboxylative C─H/N─O allylation in water was developed. When indole substrates were employed, the reaction features a broad substrate scope and good functional group tolerance. This organometallic C─H activation was also tolerant to air and water. Moreover, this versatile C─H allylation was also successfully applied to the amino acids and aryl ketimines, delivering the allylation products in good yields with high levels of chemo- and regio-selectivities. In the sixth project, a synergistic Brønsted acid/manganese(I)-catalyzed C─H hydroarylation with high chemo- and regio-selectivities in continuous flow was accomplished. With the assistance of carboxylic acid, the undesired β-O elimination could be avoided and provided a robust access to allylic carbonates in high yields with excellent chemo- and regio-selectivities. Mechanistic findings indicated that a fast organometallic C─H metalation step, as well as an intramolecular proton transfer was involved. In the last project, we have developed versatile C─C activations in water by inexpensive and Earth-abundant manganese catalysis. The organometallic C─C functionalizations, including C─C allylations, C─C alkenylations, and C─C alkylations, occurred efficiently in environmentally-benign solvent with excellent levels of chemo-, regio-, and position-selectivities. This result was showcased by the synthesis of 1,2,3-tri-substituted arenes, which could not be achieved by C─H activation.

Deuteration of arylthianthren-5-ium triflates with CD3OD or CD3OD/CD3COCD3 in the presence of Cs2CO3 by palladium catalysis or photoirradiation allowed the convenient synthesis of deuterated arenes in good yields. The Pd-catalyzed reaction generally gave better yields than the photoinduced deuteration, but exceptions also exist. They could complement each other in some cases. These reactions featured eco-friendly conditions, simplicity, inexpensive deuterium sources, good functional group tolerance, and a range of substrates. Since arylthianthren-5-ium salts could be readily synthesized from arenes and thianthrene 5-oxide, this protocol provided a formal aromatic C-H deuteration with high selectivity, enabling efficient deuterium labeling of multifunctionalized arenes and drug molecules.

The dearomatizing annulation reaction is a significant challenge in organic chemistry. The direct activation of α-carbons of simple saturated esters, as nucleophiles, is an important synthesis strategy. In the present study, we disclose [3 + 2] dearomatizing annulation reactions with direct activating α-carbons of saturated carboxylic esters and N-iminoisoquinolinium ylides, which possess highly enantioselective characteristics, catalyzed by N-heterocyclic carbenes (NHCs). The protocol achieves isoquinoline dearomatization and the construction of tricyclic chiral products under mild conditions with good yield, substrate tolerance, and diastereoselectivity as well as excellent enantioselectivity.

A Fruitful Decade of Organofluorine Chemistry: New Reagents and Reactions

General and Efficient C–P Bond Formation by Quantum Dots and Visible Light

Copper-Catalyzed Highly Enantioselective 1,4-Protoboration of Terminal 1,3-Dienes

Design, Synthesis, and Applications of <i>ortho</i> -Sulfur Substituted Arylphosphanes

Azoxy-, azo- and amino-aromatics are among the most widely used building blocks in materials science pharmaceuticals and synthetic chemistry, but their controllable and green synthesis has not yet been well established. Herein, a facile potential-tuned electrosynthesis of azoxy-, azo- and amino-aromatics via aqueous selective reduction of nitroarene feedstocks over a CoP nanosheet cathode is developed. A series of azoxy-, azo- and amino-compounds with excellent selectivity, good functional group tolerance and high yields are produced by applying different bias input. The synthetically significant and challenging asymmetric azoxy-aromatics can be controllably synthesized in moderate to good yields. The use of water as the hydrogen source makes this strategy remarkably fascinating and promising. In addition, deuterated aromatic amines with a high deuterium content can be readily obtained by using D2O. By pairing with anodic oxidation of aliphatic amines to nitriles, synthetically useful building blocks can be simultaneously produced in a CoP||Ni2P two-electrode electrolyzer. Only 1.25 V is required to achieve a current density of 20 mA cm−2, which is much lower than that of overall water splitting (1.70 V). The paired oxidation and reduction reactions can also be driven using a 1.5 V battery to synthesize nitrile and azoxybenzene with good yields and selectivity, further emphasizing the flexibility and controllability of our method. This work paves the way for a promising approach to the green synthesis of valuable chemicals through potential-controlled electrosynthesis.

Three different annulation modes of (Z)-4-aryl-4-oxo-2-(pyridin-2-yl)but-2-enenitrile in the reaction with methyl nitroacetate were discovered, allowing selective access to diverse heterocycles such as quinolizin-4-one, isoxazole, and indolizine with unique substitution patterns in good yields. Ease of operation, good chemical yields, and good functional group tolerance of our protocol enabled us to rapidly construct a number of synthetic analogs based on each scaffold under three reaction conditions.

Indanones are ubiquitous in biologically active compounds. Intramolecular hydroacylation of aldehydes and alkenes is an efficient and atom-economic route to indane rings. However, these reactions are limited to the transfer of a hydride to the alkene. The transfer of aryl groups enabling the formation of C-C bonds during the cyclization would be a new method for the synthesis of substituted indanones. This report describes the regiodivergent carboacylation of alkenes with ketones to furnish both 2- and 3-substituted indanones in a regiocontrolled manner. The regioselectivity is controlled by the careful selection of different transition-metal catalysts. Moreover, both transformations show high atom economy and good functional group tolerance, which may have implications for C-C bond cleavage in the preparation of complex cyclic molecules.

Selective functionalization of allylic C–H bonds into other chemical bonds is among the most straightforward and attractive, yet challenging transformations. Herein, a transition-metal-free protocol for direct allylic C–H nitrogenation, oxygenation, and carbonation of alkenes by thianthrenation was developed. This operationally simple protocol allows for the unified allylic C–H amination, esterification, etherification, and arylation of vinyl thianthrenium salts. Notably, the reaction furnishes multialkyl substituted allylic amines, ammonium salts, sulfonyl amides, esters, and ethers in good yields. The reaction proceeds under mild conditions with excellent functional group tolerance and could be applied to late-stage allylation of natural products, drug molecules and peptides with excellent chemoselectivity.

The cover picture depicts a preparation method of fluorescent polyaryl 2‐(pyridin‐2‐yl) phenol‐based four‐coordinate organoboron complexes, which display bright fluorescence, large Stokes shifts, and good quantum yields. In the cover, cool luminescent effects are used to highlight the strong fluorescence of fluorescent organic boron complexes. In this paper, a family of polyaryl 2‐(pyridin‐2‐yl)phenol‐based four‐coordinate organoboron complexes were prepared in good yields via deconstructive cycloaromatization of indolizines, cyclopropenones, and boric acids. The photoluminescence measurements have revealed that these N,O π‐conjugated tetracoordinate boron complexes display bright fluorescence, large Stokes shifts, and good quantum yields (Φlum = 0.15—0.45). In addition, DFT calculations were carried out to deepen the understanding of the electronic structures and optoelectronic properties of these structurally unprecedented tetracoordinate boron complexes. More details are discussed in the article by Cao et al. on page 924—930.image

SummaryTransition metal catalyzed [3 + 2] annulation of imines with double bonds via directed C-H activation offers a direct access to amino cyclic motifs. However, owing to weak coordination and steric hindrance, trifluoromethylated ketimines have been an unaddressed challenge for TM-catalyzed annulations. Here, a rhenium-catalyzed [3 + 2] annulation of trifluoromethylated ketimines with isocyanates via C(sp2)-H activation has been disclosed. This approach provides an efficient platform for rapid access to a privileged library of CF3-containing iminoisoindolinones and polyamides by utilizing challenging CF3-ketimines as the annulation component. The capability of gram scale synthesis, the post-functionalization of the cyclization adduct, the derivation of complex natural molecules and the facile synthesis of polyamides highlight a diversity of synthetic potential of the current methodology.

It is generally acknowledged that polyfluoroarenes are important fluorinated structural units for various organic molecules, such as pharmaceuticals, agrochemicals, and organic materials. Polyfluorinated aryl alkynes and alcohols are also powerful building blocks in chemical synthesis because of their versatility to be transformed into various useful molecules and also their ubiquity in natural product synthesis. Efficient methods for the synthesis of polyfluorinated aryl alkynes and alcohols are presented in Chapter 2 and Chapter 3. In addition, 3-amino-indoles have found a broad applications in medicinal chemistry as effective anticancer agents, compounds with analgesic properties and can function as potent inhibitors of tubulin polymerization, and agents for the prevention of type II diabetes. A simple method for the synthesis of 3-amino-indoles via the annulation reaction of polyfluorophenylboronates with DMF is reported in Chapter 4. Chapter 2 In Chapter 2, a mild process for the copper-catalyzed oxidative cross-coupling of electron-deficient polyfluorophenylboronate esters with terminal alkynes (Scheme S-1) is reported. This method displays good functional group tolerance and broad substrate scope, generating cross-coupled alkynyl(fluoro)arene products in moderate to excellent yields. This copper-catalyzed reaction was conducted on a gram scale to generate the corresponding product in good yield (72%). Scheme S-1. Copper-catalyzed oxidative cross-coupling of terminal alkynes with polyfluorophenylboronate esters. Based on previous reports and the aforementioned observations, a plausible catalytic cycle for this oxidative cross-coupling reaction is shown in Scheme S-2. The first step involves the addition of an alkynyl anion to Cu leading to the formation of alkynylcopper(II) species B. Subsequent transmetalation between ArFBpin and intermediate B occurs to form intermediate C. The desired product 3a is generated by eductive elimination. Finally, the oxidation of Cu(0) to Cu(II) with DDQ and Ag2O regenerates A to complete the catalytic cycle. Scheme S-2. Proposed mechanism of copper(II)-catalyzed oxidative cross-coupling between terminal alkynes and polyfluorophenylboronate esters. Chapter 3 In Chapter 3, A convenient and efficient protocol for the transition metal-free 1,2-addition of polyfluoroaryl boronate esters to aldehydes and ketones is reported, which provides secondary alcohols, tertiary alcohols, and ketones (Scheme S-3). The distinguishing features of this procedure include the employment of commercially available starting materials and the broad scope of the reaction with a wide variety of carbonyl compounds giving moderate to excellent yields. Scheme S-3. Base-promoted 1,2-addition of polyfluorophenylboronates to aldehydes and ketones. Control experiments were carried out to gain insight into the reaction mechanism. The reaction of 2a with pentafluorobenzene 5 under standard conditions was examined, yet 3a was not formed in any detectable amounts (Scheme S-4a), indicating that the C-Bpin moiety is essential and deprotonation of the fluoroarene or nucleophilic attack at the fluoroarene by the base is not a plausible pathway. Interestingly, for the standard reaction between 1a and 2a, the yield dropped dramatically if 18-crown-6 ether and K2CO3 were added (Scheme S-4b). This experimental result indicates that the presence of the potassium ion plays a crucial role for the outcome of the reaction. Furthermore, if the reaction of 1a and 2a was performed in the presence of only a catalytic amount of K2CO3 (20 mol%) (Scheme S-4c), reaction rates were reduced, and a week was required to produce 3a in good yield. This finding again indicates that the potassium ion (or the base) plays an important role in the reaction. Substituting ortho-fluorines by ortho-chlorines, using either C6Cl5Bpin 2,6-dichlorophenyl-1-Bpin as substrates, did not yield any product as shown by in situ GCMS studies. Scheme S-4. Control experiments. Based on DFT calculations, a mechanism for the 1,2-addition of polyfluorophenylboronates to aryl aldehydes in the presence of K2CO3 as base is proposed, as shown in Scheme S-5. K2CO3 interacts with the Lewis-acidic Bpin moiety of substrate 1 to generate base adduct A, which weakens the carbon-boron bond and ultimately cleaves the BC bond along with attachment of a potassium cation to the aryl group. The resulting ArF- anion adduct B undergoes nucleophilic attack at the aldehyde carbon atom of substrate 2 to generate methanolate C. The methanolate oxygen atom then attacks the electrophilic Bpin group to obtain compound D. Transfer of K2CO3 from intermediate D to the boron atom of the more Lewis-acidic polyfluorophenyl-Bpin 1 finally closes the cycle and regenerates complex A. Thus, the primary reaction product is the O-borylated addition product E, which was detected by HRMS and NMR spectroscopy for the perfluorinated derivative. Scheme S-5. Proposed mechanism of the 1,2-addition of polyfluorophenylboronates to aldehydes and ketones. Chapter 4 Chapter 4 presents a novel protocol for the transition metal-free addition and annulation of polyfluoroarylboronate esters to DMF, which provides 3-aminoindoles and tertiary amines in moderate to excellent yields (Scheme S-6). Scheme S-6. Annulation and addition reactions of polyfluorophenylboronates with DMF. While exploring the application of this strategy in synthesis, perfluorophenylBpin reacted smoothly with ethynylarenes and DMF to afford propargylamines with moderate to excellent yields (Scheme S-7). Scheme S-7. Three-component cross-coupling reaction for the synthesis of propargylamines.

The Morita‐Baylis‐Hillman (MBH) reaction has attracted great attention to generate densely functionalized adducts with promising synthetic utility and biological activities. In this work we demonstrate, for the first time, the synthesis of a series of new lipophilic hydroxylated α ‐alkyl γ ‐nitroesters, advanced γ ‐aminobutyric acid (GABA) intermediates, using the Morita‐Baylis‐Hillman (MBH) reaction as key step. The results show that the long‐chain MBH adducts can be synthesized in good yields in a metal‐free organocatalytic system in the presence of aliphatic aldehydes and activated alkenes, acrylonitrile or methyl acrylate. Followed, the Michael addition of nitromethane to MBH adducts resulted in hydroxylated α ‐alkyl γ ‐nitroesters in good yields. Thus, the key MBH reaction led to new lipophilic GABA advanced intermediates in good overall yields from aliphatic aldehydes, demonstrating the potential of this reaction pathway towards the synthesis of new drug molecules for the treatment of psychiatric or neurodegenerative disorders.