Pui Ying Choy

Advances and Applications in Organocatalytic Asymmetric aza‐Michael Addition

The stereocontrolled construction of chiral carbon–carbon bonds and carbon–heteroatom bonds are topics of paramount importance in modern organic synthesis. The importance has been driven predominantly by optically active compounds in natural products and pharmaceuticals. The success of asymmetric organocatalysis can be attributed to the advantages of their availability and their capacity to perform asymmetric transformations in a metal-free environment, under mild and non-inert reaction conditions. Asymmetric organocatalysis, using small chiral organic molecules as enantioselective catalysts, has experienced an impressive growth and is now considered the “third pillar” of enantioselective catalysis together with biocatalysis and metal catalysis. Among the great variety of organocatalytic asymmetric transformations, Michael additions occupy a very important position and have received widespread attention for accessing a variety of chiral synthetically useful building blocks. In particular, the Michael addition of nitrogen-based nucleophiles to a,b-unsaturated carbonyl systems, also termed the aza-Michael reaction, represents an especially interesting variant since it is a versatile method for constructing a new C N bond and constitutes; an important step in the synthesis of bioactive natural compounds. During the past decade, a number of elegant organocatalysts have been developed for enantiocontrol in a large variety of reactions. Accordingly, the organocatalytic asymmetric aza-Michael addition has been a very active field of research, the previous progress of which has also been the subject to some excellent reviews. The majority of organocatalytic reactions are amine catalystbased and proceed via enamine or iminium intermediates, or the amine acts as a base. Therefore, a possible competition between the catalyst and the nitrogen-based nucleophile exists in the organocatalytic aza-Michael addition. This could compromise the enantioselectivity of the reaction and remains as one of the difficulties in developing organocatalytic asymmetric aza-Michael addition. Consequently, the appropriate choices of the nitrogen-based nucleophile and the catalyst system represent a critical factor in the organocatalytic asymmetric azaMichael addition. Encouragingly, significant progress has been made in the past several years towards achieving organocatalytic asymmetric aza-Michael additions during the rapid development of asymmetric organocatalysis. Many new substrates have been applied accordingly in this transformation, together with the new approaches developed for the purpose of targetand diversity-oriented asymmetric synthesis. Based on the comprehensive work of Enders, the process made in organocatalytic asymmetric aza-Michael addition between 2010 and early 2012 are surveyed in this review. The review is also organized according to the catalyst system used.

A Radical Process towards the Development of Transition‐Metal‐Free Aromatic CarbonCarbon Bond‐Forming Reactions

Transition-metal-free cross-coupling reactions have been a hot topic in recent years. With the aid of a radical initiator, a number of unactivated arene C-H bonds can be directly arylated/functionalized by using aryl halides through homolytic aromatic substitution. Commercially available or specially designed promoters (e.g. diamines, diols, and amino alcohols) have been used to make this synthetically attractive method viable. This protocol offers an inexpensive, yet efficient route to aromatic C-C bond formations since transition metal catalysts and impurities can be avoided by using this reaction system. In this article, we focus on the significance of the reaction conditions (e.g. bases and promoters), which allow this type of reaction to proceed smoothly. Substrate scope limitations and challenges, as well as mechanistic discussion are also included.

Palladium-Catalyzed ortho-CH-Bond Oxygenation of Aromatic Ketones

A palladium-catalyzed C((sp2))-H bond oxygenation reaction is described. This protocol represents the first example of a C-H bond cleavage/C-O bond formation sequence, by employing a ketone moiety as the directing group. With this new catalytic method, a variety of ortho-acylphenols can be easily accessed from arylketones.

Palladium-Catalyzed Direct and Regioselective C−H Bond Functionalization/Oxidative Acetoxylation of Indoles†

The first general examples of palladium-catalyzed direct and selective oxidative C3-acetoxylation of indoles are presented. The mild reaction conditions (70 °C and with weak base, KOAc) in this indole C-H-acetoxylation are notable.

A decade advancement of transition metal-catalyzed borylation of aryl halides and sulfonates

This review describes the recent advancement of transition metal-catalyzed aromatic carbon-boron bond construction processes. The efficacy of palladium, nickel and copper catalysis are comparatively illustrated. Particular focus is placed on the application of ligands, for instance tailor-made phosphines and carbenes that can effectively enable the borylation of challenging and sterically demanding substrates. Selected applications of this methodology for the synthesis of pharmaceutically useful and materially interesting molecules are mostly documented. This review includes literatures up to late 2012.

Remarkably Effective Phosphanes Simply with a PPh2 Moiety: Application to Pd‐Catalysed Cross‐Coupling Reactions for Tetra‐ortho‐substituted Biaryl Syntheses

ortho-Substituted biaryl compounds are important structural motifs present in a number of natural products from various origins and have a wide range of biological properties. The biaryl substructures in vancomycin, a glycopeptide antibiotic from Streptomyces orientalis, steganacin, a cytotoxic tubulin-binding dibenzocyclootadiene lignan from Steganotaenia araliacea, and michellamine B, an anti-HIV naphthylisoquinoline alkaloid from Ancistrocladus abbreviatus, have aroused the interest of many synthetic chemists within the field of sterically congested biaryl synthesis. However, the ability to prepare extremely hindered asymmetric biaryl compounds by using Suzuki–Miyaura coupling reactions has proven to be an extremely difficult task. Recent superb findings by the Buchwald group have demonstrated that PCy2-substituted phenanthrene-based phosphanes and 2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl (S-Phos) are effective ligands for the synthesis of tetra-ortho-substituted biaryl compounds, mainly from aryl bromides (Figure 1). To date, in the exploration of phosphane ligands, only the ruthenocenylphosphane R-Phos developed by Hoshi/Hagiwara and, very recently, the diazaphospholidine chloride disclosed by Ackermann allowed the successful synthesis of tetra-ortho-substituted biaryls from unactivated aryl chlorides (Figure 1). Besides phosphanes, carbene IBiox12·OTf with a tuneable ring size, “flexible-steric-bulk” PEPPSI-IPent and phenanthryl-based H2-ICP·HCl, reported by Glorius, [10] Organ and Ma/ Andrus, respectively, are also appropriate for sterically congested couplings (Figure 1). The lore in the field of demanding cross-coupling reactions reveals that successful phosphane ligands often contain dialkylphosphane groups, such as PCy2 or PtBu2 (Figure 1). In contrast to ArPCy2 and ArPtBu2 ligands, the corresponding ArPPh2 compounds have received less attention due to the accepted rationale indicating that they are less electronrich and less bulky than the corresponding ArPCy2 and ArPtBu2 compounds (Figure 2) [13] and, thus, provide a less favourable outcomes for the oxidative addition and reductive elimination steps in unactivated aryl chloride couplings. However, triarylphosphanes are attractive compounds as they are reasonably air stable and can be readily prepared from the relatively inexpensive Ph2PCl. [17] Herein, we report an unexpected finding that advances coupling technology by showing that the previously omitted triarylphosphane family can effectively deal with difficult coupling reactions. We disclose their ability to perform the most difficult biaryl cou[a] C. M. So, W. K. Chow, P. Y. Choy, Prof. Dr. C. P. Lau, Prof. Dr. F. Y. Kwong State Key Laboratory of Chiroscience and Department of Applied Biology and Chemical Technology The Hong Kong Polytechnic University Hung Hom, Kowloon, Hong Kong (Hong Kong) Fax: (+852) 2364-9932 E-mail : bcfyk@inet.polyu.edu.hk Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201000723.

Synthesis of 3‑Cyanoindole Derivatives Mediated by Copper(I) Iodide Using Benzyl Cyanide

Copper-mediated direct and regioselective C3-cyanation of indoles using benzyl cyanide as the cyanide anion source is presented. A wide range of indoles undergo cyanation smoothly by employing a reaction system of copper(I) iodide under open-to-air vessels.

Palladium‐Catalyzed Sonogashira Coupling of Aryl Mesylates and Tosylates

Aryl alkynes are important synthetic precursors and subunits for a range of pharmaceutically attractive and valued materials science organic compounds. One of the most straightforward and versatile protocols for the construction of Csp2 Csp bond is the palladium-catalyzed cross-coupling of aryl halides/sulfonates and terminal alkynes, namely, Sonogashira coupling. This methodology features a modular approach to assemble an array of diversified compounds from commonly available electrophilic and nucleophilic partners. A number of palladium catalyst systems have been developed for facilitating the Sonogashira coupling to proceed even without Cu cocatalyst and at room temperature, as well as showing the applicability of aryl chloride substrates. Although the alkyne coupling of aryl halides has been extensively established, the popularity of aryl triflates has been limited. These constraints are possibly due to the high cost of the triflating agent (e.g., Tf2O), [7] and the low hydrolytic stability of aryl triflates under basic coupling reaction conditions. In fact, it is worth developing methods for phenolic compound derivatives to be used as electrophiles. Since they usually offer different or unique substituted groups in the aromatic ring, in which the corresponding aryl halides are not commonly available, or require additional synthetic steps to manipulate the pattern of complementary substitution. Thus, the exploration of less expensive, yet more stable, aryl arenesulfonates in Sonogashira coupling is highly favorable. Nevertheless, the higher stability of aryl arenesulfonate (e.g., aryl tosylate) makes this less reactive when used for oxidative addition under palladium catalytic system. Thus, the use of Csp2-tosylates as coupling partners in Csp2 Csp bond-forming reaction has seldom been reported. Only vinyl tosylates were successful in this transformation. Recently, the Sonogashira coupling of strongly activated and electron-deficient paraand meta-substituted aryl tosylates was disclosed using the Pd/X-Phos (X-Phos =2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl) complex in propionitrile at reflux. These pioneering examples required the slow addition of diluted alkyne substrates for 8 h over the course of reaction. Moreover, it was found that a high purity of the aryl tosylates was a prerequisite for these successful couplings. To the best of our knowledge, an operationally simple and general procedures for Sonogashira coupling of nonactivated aryl and heteraryl tosylates remains sporadically reported to date. A European patent described the application of a PdACHTUNGTRENNUNG(TFA)2/Josiphos-type (Josiphos =1-[2-(dicyclohexylphosphino)ferrocenyl]ethyldiphenylphosphine) ligand system for this reaction. Herein, we report a general and efficient catalyst system for aryl tosylates in Csp2 Csp couplings. In particular, we also uncover the first examples of more difficult, but more atom-economical aryl mesylate couplings with alkynes. We embarked on developing a general protocol for Sonogashira coupling of aryl tosylates by using an unactivated 4tert-butylphenyl tosylate and 1-heptyne as the model substrates (Table 1). Alcoholic solvents such as tBuOH were our preference instead of nitrile solvents. Commonly wellrecognized and commercially available phosphine ligands, such as DitBuPF, cataCXium A, cataCXium PCy, and XPhos, were initially screened to test the feasibility of the aryl tosylate–alkyne coupling (Table 1, entries 1–4). Moderate substrate conversions and fair product yields were afforded by using biaryl-type monodentate phosphines as the supporting ligands (Table 1, entries 3 and 4). A combination of Pd ACHTUNGTRENNUNG(OAc)2 with CM-phos was found to be the best catalyst system for this tosylate coupling (Table 1, entry 5). A survey of often used inorganic bases revealed that K3PO4 and K3PO4·H2O were equally efficient (Table 1, entries 5–8). The best Pd/CM-phos ratio was found to be 1:3 (Table 1, entries 5, 10, and 11). [a] P. Y. Choy, W. K. Chow, C. M. So, Prof. Dr. C. P. Lau, Prof. Dr. F. Y. Kwong State Key Laboratory of Chiroscience and Department of Applied Biology and Chemical Technology The Hong Kong Polytechnic University, Hung Hom Kowloon, Hong Kong (Hong Kong) Fax: (+852) 2364-9932 E-mail : bcfyk@inet.polyu.edu.hk Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201001269.

Copper-Catalyzed Oxidative C–H Amination of Tetrahydrofuran with Indole/Carbazole Derivatives

A simple α-C-H amination of cyclic ether with indole/carbazole derivatives has been accomplished by employing copper(II) chloride/bipy as the catalyst system. In the presence of the di-tert-butyl peroxide oxidant, cyclic ethers such as tetrahydrofuran, 1,4-dioxane, and tetrahydropyran successfully undergo C-H/N-H cross dehydrogenative coupling (CDC) with various carbazole or indole derivatives in good-to-excellent yields.

Oxidative coupling between C(sp2)–H and C(sp3)–H bonds of indoles and cyclic ethers/cycloalkanes

Cross-dehydrogenative-coupling (CDC) between C-H/C-H bonds of indoles and cyclic ethers/cycloalkanes is made viable through a simple transition-metal-free pathway. With the aid of only di-tert-butyl peroxide, a number of inactive cyclic ethers and cycloalkanes can be directly coupled with indole derivatives in satisfactory yields.