Yu-Feng Liang

PdCl2 and N‐Hydroxyphthalimide Co‐catalyzed C sp 2H Hydroxylation by Dioxygen Activation

Direct functionalization of C H bonds has been developed as a powerful strategy to form new chemical bonds. Among them, transition-metal-catalyzed hydroxylation of C H bonds has received considerable attention because of the industrially important alcohol or phenol products. 3] Despite the significant development in the past decades, 2] catalytic hydroxylation of Csp2 H bonds still remains a very challenging task. With regard to green chemistry, molecular oxygen is regarded as an ideal oxidant because of its natural, inexpensive, and environmental friendly characteritics. In 1990, Fujiwara and co-workers disclosed a Pd(OAc)2-catalyzed hydroxylation of benzene with molecular oxygen (Scheme 1a). However, this reaction is limited by low efficiency (2.3%), poor selectivity, and harsh reaction conditions (15 atm O2, 15 atm CO, 180 8C). To control the selectivity and improve the efficiency, Yu and co-workers used a carboxyl group as the directing group and realized the direct hydroxylation of arenes with molecular oxygen (1 atm) in the presence of a benzoquinone oxidant (1.0 equiv) and base (1.0 equiv; Scheme 1 b). Nevertheless, for substrates with other directing groups, the transition-metal-catalyzed direct hydroxylation is still difficult (Scheme 1 c). Alternatively, a hydrolysis process assisted by various stoichiometric oxidants (potassium persulfates or periodides) for substrates with carbonyl groups was disclosed by the groups of Rao, Dong, Kwong, and Ackermann (Scheme 1c). Functionalized 2-(pyridin-2-yl)phenols are useful building blocks for preparing light-emitting materials and bioactive molecules. Recent development for the synthesis of these compounds was realized by this hydrolysis strategy through R-OAc intermediates. Thus, it would be attractive to synthesize 2-(pyridin-2-yl)phenols by direct hydroxylation of a C H bond with O2 under neutral reaction conditions. Herein, we disclose a novel PdCl2 and NHPI (N-hydroxyphthalimide) cocatalyzed, direct Csp2 H hydroxylation of 2phenylpyridines (Scheme 1d). The significance of the present chemistry is threefold: 1) This process is a novel transition metal and organocatalyst cocatalyzed Csp2 H functionalization using a radical process. A unique and reasonable mechanism is proposed for this reaction, which will probably promote the development of Csp2 H functionalization by the combination of a radical process with a transition-metal catalysis. 2) To the best of our knowledge, this reaction is a novel pyridyl group directed hydroxylation with O2, thus leading to useful products for preparing various biologically active molecules, organic, and light-emitting materials. 3) Molecular oxygen is employed as a reagent and the sole oxidant under neutral conditions without the addition of any other stoichiometric oxidant and base, thus making this protocol very green and practical. Inspired by our previous work on aerobic oxidation by peroxide radical intermediates, we started our model study by investigating the direct C H hydroxylation of 2-phenylpyridine (1a). To our delight, when the reaction was conducted under O2 using PdBr2 and NHPI as cocatalysts at 100 8C in toluene, the desired ortho-hydroxylation product 2a was obtained in 54% yield (Table 1, entry 1). The screening on different palladium catalysts shows that PdCl2 performed with high efficiency (entry 5). If TBHP (2.0 equiv) instead of NHPI was employed, the yield decreased slightly (entry 6), and the reaction did not work in the presence of TEMPO (10 mol %; entry 7). The additives such as base, Brønsted acids, Lewis acids, and ligands did not improve the efficiency Scheme 1. Hydroxylation of Csp2 H bonds. BQ= benzoquinone, DG= directing group.

Mn-Catalyzed Highly Efficient Aerobic Oxidative Hydroxyazidation of Olefins: A Direct Approach to β-Azido Alcohols

An efficient Mn-catalyzed aerobic oxidative hydroxyazidation of olefins for synthesis of β-azido alcohols has been developed. The aerobic oxidative generation of azido radical employing air as the terminal oxidant is disclosed as the key process for this transformation. The reaction is appreciated by its broad substrate scope, inexpensive Mn-catalyst, high efficiency, easy operation under air, and mild conditions at room temperature. This chemistry provides a novel approach to high value-added β-azido alcohols, which are useful precursors of aziridines, β-amino alcohols, and other important N- and O-containing heterocyclic compounds. This chemistry also provides an unexpected approach to azido substituted cyclic peroxy alcohol esters. A DFT calculation indicates that Mn catalyst plays key dual roles as an efficient catalyst for the generation of azido radical and a stabilizer for peroxyl radical intermediate. Further calculation reasonably explains the proposed mechanism for the control of C-C bond cleavage or for the formation of β-azido alcohols.

Cationic Cobalt(III)-Catalyzed Aryl and Alkenyl CH Amidation: A Mild Protocol for the Modification of Purine Derivatives

A cationic cobalt(III)-catalyzed direct C-H amidation of unactivated (hetero)arenes and alkenes by using 1,4,2-dioxazol-5-ones as the amidating reagent has been developed. This transformation proceeds efficiently under external oxidant-free conditions with a broad substrate scope. Moreover, 6-arylpurine compounds, which often exhibit high potency in antimycobacterial, cytostatic, and anti-HCV activities, can be smoothly amidated, thus offering a mild protocol for their late stage functionalization.

CuI-Nanoparticles-Catalyzed Selective Synthesis of Phenols, Anilines, and Thiophenols from Aryl Halides in Aqueous Solution

CuI-nanoparticles-catalyzed selective synthesis of phenols, anilines, and thiophenols from aryl halides was developed in the absence of both ligands and organic solvents. Anilines were formed selectively with ammonia competing with hydroxylation and thiophenols were generated selectively with sulfur powder after subsequent reduction competing with hydroxylation and amination.

Highly Efficient CH Hydroxylation of Carbonyl Compounds with Oxygen under Mild Conditions

A transition-metal-free Cs2 CO3 -catalyzed α-hydroxylation of carbonyl compounds with O2 as the oxygen source is described. This reaction provides an efficient approach to tertiary α-hydroxycarbonyl compounds, which are highly valued chemicals and widely used in the chemical and pharmaceutical industry. The simple conditions and the use of molecular oxygen as both the oxidant and the oxygen source make this protocol very environmentally friendly and practical. This transformation is highly efficient and highly selective for tertiary C(sp(3) )H bond cleavage.

I2- or NBS-Catalyzed Highly Efficient α-Hydroxylation of Ketones with Dimethyl Sulfoxide

An efficient method for the direct preparation of high synthetic valuable α-hydroxycarbonyls is described. The simple and readily available I2 or NBS was used as catalyst. DMSO acts as the oxidant, oxygen source, and solvent. A diverse range of tertiary Csp(3)-H bonds as well as more challenging secondary Csp(3)-H bonds could be hydroxylated in this transformation. The reaction is mild, less toxic and easy to perform.

Synergistic Gold and Iron Dual Catalysis: Preferred Radical Addition toward Vinyl-Gold Intermediate over Alkene.

A dual catalytic approach enlisting gold and iron synergy is described. This method offers readily access to substituted heterocycle aldehydes via oxygen radical addition to vinyl-gold intermediates under Fe catalyst assistance. This system shows good functional group compatibility for the generation of substituted oxazole, indole, and benzofuran aldehydes. Mechanistic evidence greatly supports selective radical addition to an activated vinyl-Au double bond over alkene. This unique discovery offers a new avenue with great potential to further extend the synthetic power and versatility of gold catalysis.

Cu- or Fe-catalyzed C–H/C–C bond nitrogenation reactions for the direct synthesis of N-containing compounds

Nitrogen-containing compounds are widely present in both natural products and synthetic compounds, for example, they show up within functional materials, top-selling drugs, as well as bioactive molecules. Thus, organic chemists have paid considerable attention in developing novel methodologies for their preparation. To synthesize these compounds in a green and sustainable way, researchers have focused on the direct functionalization of hydrocarbons via C–H and/or C–C bond cleavage. Although significant progress has been made in the direct functionalization of simple hydrocarbons, direct incorporation of N-atoms into simple substrates via C–H and/or C–C bond cleavage remains challenging due to the inert chemical bonds and the unstable character of some N-sources under oxidative conditions. Azide reagents are frequently used as nitrogen source in incorporating nitrogen into carbon skeletons. Although the exact reaction pathway remains unclear, detailed mechanistic studies revealed that the carbon cation containing the azido group may exist as the key intermediate which would undergo Schmidt-type rearrangement to afford nitriles, tetrazoles, arylamines, or other kinds of nitrogen-containing compounds. Considering the high cost and toxicity of heavy metals, copper and iron, as inexpensive, readily accessible metals have already shown their unique utilities. This account attempts to focus on C–H/C–C bond nitrogenation reactions via Cu and Fe catalysis, as well as their applications in synthetic chemistry.

Oxygenation via C–H/C–C Bond Activation with Molecular Oxygen

The selective oxidation of organic molecules is a fundamentally important component of modern synthetic chemistry. In the past decades, direct oxidative C-H and C-C bond functionalization has proved to be one of the most efficient and straightforward methods to synthesize complex products from simple and readily available starting materials. Among these oxidative processes, the use of molecular oxygen as a green and sustainable oxidant has attracted considerable attention because of its highly atom-economical, abundant, and environmentally friendly characteristics. The development of new protocols using molecular oxygen as an ideal oxidant is highly desirable in oxidation chemistry. More importantly, the oxygenation reaction of simple molecules using molecular oxygen as the oxygen source offers one of the most ideal processes for the construction of O-containing compounds. Aerobic oxidation and oxygenation by enzymes, such as monooxygenase, tyrosinase, and dopamine β-monooxygenase, have been observed in some biological C-H bond hydroxylation processes. Encouraged by these biological transformations, transition-metal- or organocatalyst-catalyzed oxygenation through dioxygen activation has attracted academic and industrial prospects. In this Account, we describe some advances from our group in oxygenation via C-H/C-C bond activation with molecular oxygen as the oxidant and oxygen source for the synthesis of O-containing compounds. Under an atmosphere of O2 (1 atm) or air (1 atm), we have successfully incorporated one or two O atoms from O2 into simple and readily available substrates through C-H, C-C, C═C, and C≡C bond cleavage by transition-metal catalysis, organocatalysis, and photocatalysis. Moreover, we have devised cyclization reactions with molecular oxygen to construct O-heterocycles. Most of these transformations can tolerate a broad range of functional groups. Furthermore, on the basis of isotope labeling experiments, electron paramagnetic resonance spectral analysis, and other mechanistic studies, we have demonstrated that a single electron transfer process via a carbon radical, peroxide radical, or hydroxyl radical is involved in these aerobic oxidation and oxygenation reactions. These protocols provide new approaches for the green synthesis of various α-keto amides, α-keto esters, esters, ketones, aldehydes, formamides, 2-oxoacetamidines, 2-(1H)-pyridones, phenols, tertiary α-hydroxy carbonyls, p-quinols, β-azido alcohols, benzyl alcohols, tryptophols, and oxazoles, which have potential applications in the preparation of natural products, bioactive compounds, and functional materials. In most cases, inexpensive and low-toxicity Cu, Fe, Mn, or NHPI was found to be an efficient catalyst for the transformation. The high efficiency, low cost, high oxygen atom economy, broad substrate scope, and practical operation make the developed oxygenation system very attractive and practical. Moreover, the design of new types of molecular-oxygen- or air-based oxidation and oxygenation reactions can be anticipated.

Pd-catalyzed tandem C-H azidation and N-N bond formation of arylpyridines: a direct approach to pyrido[1,2-b]indazoles.

A novel Pd-catalyzed nitrogenation of arylpyridines via C-H azidation has been developed. Direct C-N and N-N formations are achieved for this N-atom incorporation transformation using azides as the N-atom source. This method provides an alternatively concise approach for the construction of bioactively important pyrido[1,2-b]indazoles.