Xiaoming Jie

Recent advances in directed C–H functionalizations using monodentate nitrogen-based directing groups

The use of directing groups has proven to be a successful strategy to enhance reactivity and control selectivity in C–H functionalization reactions. In the past decade, a multitude of new transformations and new directing groups have been explored, and several recent reviews have discussed directing group approaches for C–H functionalization. This review focuses specifically on the use of monodentate nitrogen-based directing groups published during the past two years, with the aim of covering a body of literature that is complementary to existing reviews.

Palladium-Catalyzed Decarboxylative CH Bond Arylation of Thiophenes†

Conventionally, 2-arylthiophenes are synthesized by cross-coupling reactions of (hetero)aryl halides with (hetero)aryl organometallic reagents. Owing to the wide applications of this family of compounds, the development of new methods for the synthesis of valuable 2-arylthiophenes from simple and readily available starting materials by concise steps continues to be a target of intense interest. In this context, the direct C H arylation of thiophenes with aryl iodides and bromides has been achieved by using Pd, Ir, Rh, and Cu catalysts; thus thiophenes were directly used to replace expensive thienyl organometallic reagents in traditional cross-coupling reactions. As a highly efficient approach to 2-arylthiophenes, the oxidative cross-coupling of two unfunctionalized arenes has been realized in the palladium-catalyzed reactions of thiophenes with C H acidic polyfluoroarenes and nitrogen-containing heteroarenes. Moreover, metal-free oxidative cross-couplings of thiophenes with electron-rich arenes has also been reported. Although these transformations represent substantial progress toward the syntheses of 2-arylthiophenes in an atom-economical and environmentally benign way, there is significant room for improvement with respect to the generality and functionalgroup tolerance of these state-of-the-art methods. On the other hand, the use of carboxylic acids as crosscoupling components by a metal-promoted decarboxylation process is a rapidly growing area of research because of their low cost, diversity, and ready availability. Recently, decarboxylative cross-coupling reactions have been expanded to decarboxylative C H bond functionalization, including intramolecular reactions for the syntheses of dibenzofurans, intermolecular reactions for the selective arylation of indoles, ortho acylation of acetanilides, the construction of azole–azole linkages, and the direct arylation of C H acidic polyfluorobenzenes. A decarboxylative C H bond functionalization that combines two newly emerging approaches, that is, decarboxylation and direct C H bond functionalization, offers a new synthetic strategy in synthesis. However, the challenges posed by this promising process remain. For example, many of the decarboxylative C H bond functionalization reactions were restricted to a narrow range of arene carboxylic acids because the reactivity of the arene carboxylic acids toward decarboxylation is very sensitive to the substitutents on benzene rings. Herein, we report the decarboxylative C H bond arylation of thiophenes catalyzed by a Pd(OAc)2/Ag2CO3 system; electron-rich, electron-deficient, and heterocyclic benzoic acids can all be used as aryl sources in this reaction and a broad spectrum of functional groups can be tolerated. As generally proposed for similar processes, the Pd/Agcatalyzed decarboxylative C H arylation of thiophenes may involve a Pd-promoted C H cleavage to form a palladium intermediate, a Ag-promoted decarboxylation to generate an aryl silver species, a subsequent aryl transfer from Ag to Pd, and reductive elimination (Scheme 2). In light of this proposal, we envisioned that the major problems impeding the execution of the target process would result from the following side reactions: 1) the unstable aryl silver intermediate is liable to protodecarboxylation and decarboxylative homocoupling if the desired cross-coupling reaction Scheme 1. Three examples illustrating the importance of compounds containing a 2-arylthiophene moiety: A natural product (A); Evista (B), a medicine used to prevent and treat osteoporosis; ITPEEPT (C), an electrochromic device.

Palladium-Catalyzed Oxidative Cross-Coupling between Heterocycles and Terminal Alkynes with Low Catalyst Loading†

Alkynylated (hetero)arenes represent a recurring structural motif found in bioactive natural products, pharmaceuticals, and organic materials. These compounds are of great importance either as building blocks or synthetic intermediates and have become increasingly attractive for synthetic organic chemists. The well-known Sonogashira reaction is one of the most commonly used methods for installing alkyne moieties into (hetero)arenes molecules. Recently, the direct alkynylation of (hetero)aromatic compounds has appeared as an alternative to the Sonogashira reaction by using the alkynyl reagents prepared from terminal alkynes, such as alkynyl halides, benziodoxolone-based hypervalent iodine reagents, or arylsulfonylacetylenes. From the viewpoint of step and atom economy, the oxidative cross-coupling between (hetero)arenes and terminal alkynes would be a straightforward and more efficient method for installing alkynyl groups into the (hetero)arene rings, because the need for prefunctionalization of the starting materials would be eliminated. In this context, a few of the seminal examples for such a transformation were recently reported, including the gold-catalyzed alkynylation of electron-rich (hetero)arenes with electron-poor terminal alkynes; the copper-, nickel-, or palladium-catalyzed alkynylation of C–H acidic polyfluoroarenes and azoles; and the palladium-catalyzed alkynylation of C3-blocked 1-methylindoles. However, these established alkynylation methods only worked for specific substrates, and a catalytic method suitable for many important heterocycles such as thiophenes and furans remains elusive. Owing to the importance of alkynylated thiophenes in material science, natural product and medicinal chemistry, as exemplified by the three alkynylated thiophene molecules illustrated in Scheme 1, the general method for cross-coupling thiophenes and other heterocycles with terminal alkynes would be highly desirable. Herein, we report a versatile method that enables the alkynylation of thiophenes bearing various functional groups and other aromatic heterocycles by applying a low loading of a palladium catalyst and using an array of terminal alkynes as alkynylating reagents. Several problems hamper the realization of oxidative cross-coupling between aromatic heterocycles and terminal alkynes. The first problem is the undesired terminal alkyne homocoupling under oxidative conditions. The slow addition of terminal alkynes to the reaction system indeed partially overcame the alkyne homocoupling problem but meanwhile brought about the operational inconvenience, 12] and the use of a large excess of the other coupling partner was capable of suppressing alkyne homocoupling, but sacrificed those reagents. 12] Very recently, the decrease of the palladium catalyst loading proved to be an effective means of overcoming alkyne homocoupling in the Pd-catalyzed cross-coupling of alkynes. Nevertheless, the low palladium catalyst loading is incompatible with the general reaction conditions for the C–H functionalization of aromatic heterocycles, in which relatively high palladium loadings (5–10 mol% Pd catalyst) are usually required to obtain satisfying yields. Hence, we speculated that the establishment of suitable reaction conditions to stabilize the Pd catalyst and enhance its catalytic activity would allow using a low catalyst loading and possibly enable selective cross-coupling reactions of aromatic heterocycles with terminal alkynes. Elegant studies on C H bond functionalization of (hetero)arenes and recent advances in metal-catalyzed oxidative cross-coupling reactions involving terminal alkynes provided useful starting points for our investigation of this direct alkynylation of thiophenes. The reaction of phenylacetylene (1a) with 2-acetylthiophene (2a) was chosen as a model system for optimization studies (Table 1). Initially, the reaction that was carried out in 1,2-dimethoxyethane (DME) at 90 8C for 4 h in the presence of Pd(OAc)2 (5 mol%) as a catalyst and Ag2CO3 (1.5 equiv) as an oxidant did not give the desired product 3a, but instead formed a large amount of unwanted alkyne homocoupling by-product 4 (Table 1, entry 1). Although the addition of K2CO3 or pivalic acid as Scheme 1. Three examples of useful alkynylated thiophenes: a) 5-(2Phenylethynyl)-2-b-glucosylmethyl-thiophene, a natural product; b) S-3304, a matrix metalloproteinase inhibitor; c) R = n-C4H9, a liquid-crystalline semiconductor.

Pd-catalyzed cross-coupling of aryl carboxylic acids with propiophenones through a combination of decarboxylation and dehydrogenation.

A Heck of a reaction: With a PCy(3)-supported Pd catalyst, aryl carboxylic acids cross-couple to saturated propiophenones through a combination of decarboxylation and dehydrogenation to give chalcones bearing a variety of functional groups in generally good yields (see scheme). Furthermore, a one-pot procedure, involving this reaction and a subsequent selective hydrogenative cyclization process, has been developed for the facile synthesis of quinoline derivatives from 2-nitrobenzoic acids.

Rh(III)-Catalyzed Amide-Directed Cross-Dehydrogenative Heteroarylation of Pyridines

A new catalytic methodology has been developed for the synthesis of heteroaryled pyridines via a rhodium(III)-catalyzed dehydrogenative cross-coupling reaction. This protocol features a good substrate scope with a broad range of functional group tolerance and high regioselectivity of the pyridyl C-H activation.

Cu-Catalyzed Sequential Dehydrogenation–Conjugate Addition for β-Functionalization of Saturated Ketones: Scope and Mechanism

The first copper-catalyzed direct β-functionalization of saturated ketones is reported. This protocol enables diverse ketones to couple with a wide range of nitrogen, oxygen and carbon nucleophiles in generally good yields under operationally simple conditions. The detailed mechanistic studies including kinetic studies, KIE measurements, identification of reaction intermediates, EPR and UV-visible experiments were conducted, which reveal that this reaction proceeds via a novel radical-based dehydrogenation to enone and subsequent conjugate addition sequence.

Dehydrogenative desaturation-relay via formation of multicenter-stabilized radical intermediates

In organic molecules, the reactivity at the carbon atom next to the functional group is dramatically different from that at other carbon atoms. Herein, we report that a versatile copper-catalyzed method enables successive dehydrogenation or dehydrogenation of ketones, aldehydes, alcohols, α,β-unsaturated diesters, and N-heterocycles to furnish stereodefined conjugated dienecarbonyls, polyenecarbonyls, and nitrogen-containing heteroarenes. On the basis of mechanistic studies, the copper-catalyzed successive dehydrogenation process proceeds via the initial α,β-desaturation followed by further dehydrogenative desaturation of the resultant enone intermediate, demonstrating that the reactivity at α-carbon is transferred through carbon–carbon double bond or longer π-system to the carbon atoms at the positions γ, ε, and η to carbonyl groups. The dehydrogenative desaturation–relay is ascribed to the formation of an unusual radical intermediate stabilized by 5- or 7,- or 9-center π-systems. The discovery of successive dehydrogenation may open the door to functionalizations of the positions distant from functional groups in organic molecules.Synthesis of valuable polyene molecules under mild conditions and with good functional groups tolerance is of paramount importance. Here, the authors show the versatile copper-catalyzed successive dehydrogenation of a variety of organic substrates affording highly conjugated unsaturated products.