Yuxin Cui

Indoles from Simple Anilines and Alkynes: Palladium-Catalyzed CH Activation Using Dioxygen as the Oxidant†

Pd doles it out: A palladium-catalyzed approach to indoles using the title reaction was achieved (see scheme). The oxidant used in this catalytic cycle was O(2). Both N-nonsubstituted and N-alkyl monosubstituted anilines can be successfully transformed into the corresponding indoles by this method.

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.

Synthesis of β- and γ-Carbolinones via Pd-Catalyzed Direct Dehydrogenative Annulation (DDA) of Indole-carboxamides with Alkynes Using Air as the Oxidant

A palladium-catalyzed direct dehydrogenative annulation (DDA) of indolecarboxamides with internal alkynes via C-H and N-H bond cleavage using air as the oxidant was developed. With this method, both beta- and gamma-carbolinones can be easily prepared under the mild conditions.

N‐Heterocyclic Carbene‐Catalyzed Homoenolate Additions with N‐Aryl Ketimines as Electrophiles: Efficient Synthesis of Spirocyclic γ‐Lactam Oxindoles

In pole position: A simple and efficient approach to spirocyclic γ-lactam oxindoles by the N-heterocyclic carbene catalyzed addition of homoenloate equivalents to N-aryl isatinimines has been developed (see scheme). The use of N-aryl isatinimines as electrophiles in the NHC-catalyzed umpolung reaction of α,β-unsaturated aldehydes is demonstrated for the first time.

Organocatalytic Asymmetric Intermolecular Dehydrogenative α-Alkylation of Aldehydes Using Molecular Oxygen as Oxidant

An organocatalytic enantioselective intermolecular oxidative dehydrogenative α-alkylation of aldehydes via benzylic C-H bond activation has been developed. The asymmetric reaction is smoothly fulfilled by using simple and green molecular oxygen as the oxidant. Two hydrogen dissociations make this transformation more environmentally benign because of high atom efficiency.

Total Synthesis of Lamellarins D, H, and R and Ningalin B

A concise total synthesis of lamellarins D (7 steps), H (7 steps), and R (5 steps) and ningalin B (5 steps) is achieved starting from the corresponding aldehydes and amines. The synthesis features three oxidative reactions as key steps in a biomimetic manner, involving an AgOAc-mediated oxidative coupling reaction to construct the pyrrole core, a Pb(OAc)(4)-induced oxidative cyclization to form the lactone, and Kitas oxidation reaction to form the pyrrole-arene C-C bond.

One-Pot AgOAc-Mediated Synthesis of Polysubstituted Pyrroles from Primary Amines and Aldehydes: Application to the Total Synthesis of Purpurone

A simple and efficient method for the synthesis of 1,3,4-trisubstituted or 3,4-disubstituted pyrroles has been developed. The reaction represents the first time that pyrroles are synthesized directly from readily available aldehydes and amines (anilines) as starting materials. This method has been successfully applied to the rapid synthesis of purpurone.

Water-Controlled Regioselectivity of Pd-Catalyzed Domino Reaction Involving a C−H Activation Process: Rapid Synthesis of Diverse Carbo- and Heterocyclic Skeletons

A palladium-catalyzed domino reaction involving a C-H activation process to synthesize diverse carbo- and heterocyclic skeletons was developed. H(2)O (as cosolvent) is used to control the regioselectivity.

Implanting Nitrogen into Hydrocarbon Molecules through CH and CC Bond Cleavages: A Direct Approach to Tetrazoles

The development of novel methods for the preparation of tetrazoles is of long-standing interest and a challenge for organic chemists because of the importance of these compounds in chemistry and biology. In particular, 1,5-disubstituted tetrazoles are very useful compounds in medicinal chemistry and important synthetic intermediates. In the past several decades, some general strategies for the synthesis of 1,5-disubstituted tetrazoles from functionalized starting materials have been developed (Scheme 1). These methods include: a) the reactions of ketones or oximes with sodium azide and hydrogen azides, b) the reactions of amides with sodium azides in the presence of phosphorus(V) chloride or triflic anhydride and the reactions of amidrazones with dinitrogen tetroxide or nitrous acid, c) the reactions of imidoyl chlorides or imidoylbenzotriazoles with sodium azides and, d) the reactions of nitriles with alkyl azides. These developed methods significantly improved the synthesis of tetrazoles, but these approaches have some limitations, such as the use of protic acid catalysts, tedious workups, and the use of functionalized starting materials, hence encouraging scientists to discover new strategies. The direct transformation of hydrocarbon molecules by transition-metal-catalyzed selective C H and C C bond activation (cleavage) has attracted considerable attention, owing not only to its fundamental scientific appeal but also to its potential utility in organic synthesis. A direct approach to tetrazoles through C H and C C bond cleavages of simple hydrocarbon molecules is still an extremely attractive yet challenging goal. Herein, we demonstrate a novel and efficient Cu-promoted implanting of nitrogen into simple hydrocarbon molecules to construct 1, 5-disubstituted tetrazoles through C H and C C bond cleavages, and C N bond formation under mild and neutral reaction conditions (Scheme 1e). Azide has been widely used as a useful aminating reagent in organic synthesis. The application of azides for the direct synthesis of aryl nitriles and alkenyl nitriles through C H bond cleavage has been recently reported. Recent achievements on the functionalization of C H and C C bonds encouraged us to try the direct synthesis of

Total Synthesis of (±)‐Decursivine and (±)‐Serotobenine: A Witkop Photocyclization/Elimination/O‐Michael Addition Cascade Approach

The ’ideal’ synthesis is pursued actively by organic chemists since it encompasses the ideas of atom, step, and redox economy. Cascade reactions offer an attractive strategy for the synthesis of complicated natural products, especially when the cyclization is a biomimetic process. Additionally, the avoidance of protecting groups is a major aspect of streamlining a synthesis. With our ongoing interest in the study of indole alkaloids and the pursuit of the ideal synthesis, we describe herein short and efficient total syntheses of the indole alkaloids ( )-decursivine (1) and ( )-serotobenine (2) that are facilitated by a cascade Witkop photocyclization/ elimination/O-Michael addition sequence (Figure 1).