Qilong Shen

Mechanically-Induced Chemical Changes in Polymeric Materials

Engineering applications of synthetic polymers are widespread due to their availability, processability, low density, and diversity of mechanical properties (Figure 1a). Despite their ubiquitous nature, modern polymers are evolving into multifunctional systems with highly sophisticated behavior. These emergent functions are commonly described as “smart” characteristics whereby “intelligence” is rooted in a specific response elicited from a particular stimulus. Materials that exhibit stimuli-responsive functions thus achieve a desired output (O, the response) upon being subjected to a specific input (I, the stimulus). Given that mechanical loading is inevitable, coupled with the wide range of mechanical properties for synthetic polymers, it is not surprising that mechanoresponsive polymers are an especially attractive class of smart materials. To design materials with stimuli-responsive functions, it is helpful to consider the I-O relationship as an energy transduction process. Achieving the desired I-O linkage thus becomes a problem in finding how to transform energy from the stimulus into energy that executes the desired response. The underlying mechanism that forms this I-O coupling need not be a direct, one-step transduction event; rather, the overall process may proceed through a sequence of energy transduction steps. In this regard, the network of energy transduction pathways is a useful roadmap for designing stimuli-responsive materials (Figure 1b). It is the purpose of this review to broadly survey the mechanical to chemical * To whom correspondence should be addressed. Phone: 217-244-4024. Fax: 217-244-8024. E-mail: jsmoore@illinois.edu. † Department of Chemistry and Beckman Institute. ‡ Department of Materials Science and Engineering and Beckman Institute. § Department of Aerospace Engineering and Beckman Institute. Chem. Rev. XXXX, xxx, 000–000 A

An Electrophilic Hypervalent Iodine Reagent for Trifluoromethylthiolation

[*] X. Shao, X.-Q. Wang, T. Yang, Prof. Dr. L. Lu, Prof. Dr. Q. ShenKey Laboratory of Organofluorine Chemistry, Shanghai Institute ofOrganic Chemistry, Chinese Academy of Sciences345 Lingling Road, Shanghai 200032 (China)E-mail: lulong@sioc.ac.cnshenql@sioc.ac.cn[**] The authors gratefully acknowledge financial support from theNational Basic Research Program of China (2012CB821600,2010CB126103), the Key Program of Natural Science Foundation ofChina (21032006), the National Natural Science Foundation ofChina (21172245/21172244/B020304), Agro-scientific Research inthe Public Interest (201103007), the National Key TechnologiesR&D Program (2011BAE06B05), the Shanghai Scientific ResearchProgram (10XD1405200), and SIOC for financial support.Supporting information for this article is available on the WWWunder http://dx.doi.org/10.1002/anie.201209817.

Highly Reactive, General and Long-Lived Catalysts for Palladium-Catalyzed Amination of Heteroaryl and Aryl Chlorides, Bromides, and Iodides: Scope and Structure−Activity Relationships

We describe a systematic study of the scope and relationship between ligand structure and activity for a highly efficient and selective class of catalysts containing sterically hindered chelating alkylphosphines for the amination of heteroaryl and aryl chlorides, bromides, and iodides. In the presence of this catalyst, aryl and heteroaryl chlorides, bromides, and iodides react with many primary amines in high yields with part-per-million quantities of palladium precursor and ligand. Many reactions of primary amines with both heteroaryl and aryl chlorides, bromides, and iodides occur to completion with 0.0005-0.05 mol % catalyst. A comparison of the reactivity of this catalyst for the coupling of primary amines at these loadings is made with catalysts generated from hindered monophosphines and carbenes, and these data illustrate the benefits of chelation. Studies on structural variants of the most active catalyst indicate that a rigid backbone in the bidentate structure, strong electron donation, and severe hindrance all contribute to its high reactivity. Thus, these complexes constitute a fourth-generation catalyst for the amination of aryl halides, whose activity complements catalysts based on monophosphines and carbenes.

Copper-Catalyzed Trifluoromethylation of Aryl and Vinyl Boronic Acids with An Electrophilic Trifluoromethylating Reagent

A copper-catalyzed trifluoromethylation of aryl- and alkenylboronic acids with Tognis reagent was described. The reaction proceeded in good to excellent yields for a range of different substrates including heteroarylboronic acids and substrates with a variety of functional groups under mild reaction conditions.

Highly Selective Trifluoromethylation of 1,3‐Disubstituted Arenes through Iridium‐Catalyzed Arene Borylation

The old one two: A sequential iridium-catalyzed borylation and copper-catalyzed trifluoromethylation of arenes is described (see scheme; Pin = pinacol). The reaction is conducted under mild reaction conditions and tolerates a variety of functional groups. The advantages of this tandem procedure are demonstrated by the late-stage trifluoromethylation of a number of biologically active molecules.

N-Trifluoromethylthiosaccharin: An Easily Accessible, Shelf-Stable, Broadly Applicable Trifluoromethylthiolating Reagent†

A new, electrophilic trifluoromethylthiolating reagent, N-trifluoromethylthiosaccharin, was developed and can be synthesized in two steps from saccharin within 30 minutes. N-trifluoromethylthiosaccharin is a powerful trifluoromethylthiolating reagent and allows the trifluoromethylthiolation of a variety of nucleophiles such as alcohols, amines, thiols, electron-rich arenes, aldehydes, ketones, acyclic β-ketoesters, and alkynes under mild reaction conditions.

Shelf-Stable Electrophilic Reagents for Trifluoromethylthiolation

Fluorine, which is the most electronegative element and has a small atomic radius, plays a key role in pharmaceutical, agrochemical, and materials sciences. One of the fluoroalkyl groups, the trifluoromethylthio group (CF3S-), has been well-recognized as an important structural motif in the design of lead compounds for new drug discovery because of its high lipophilicity (Hansch lipophilicity parameter π = 1.44) and strong electron-withdrawing properties, which could improve the drug molecules cell-membrane permeability and enhance its chemical and metabolic stability. While classic methods for the preparation of trifluoromethylthiolated compounds typically involve halogen-fluorine exchange reactions of polyhalogenomethyl thioethers or trifluoromethylation of sulfur-containing compounds under harsh reaction conditions, an alternative but more attractive strategy is direct trifluoromethylthiolation of the substrate at a late stage by employing an electrophilic trifluoromethylthiolating reagent. Although several electrophilic trifluoromethylthiolating reagents have been reported previously, these reagents either require a strong Lewis acid/Brønsted acid as an activator or suffer from a toxic nature or limited substrate scope. To address these problems, in late 2011 we initiated a project with the aim to develop new, shelf-stable, and highly reactive electrophilic trifluoromethylthiolating reagents that could easily install the trifluoromethylthio group at the desired positions of the drug molecule at a late stage of drug development. Inspired by the broad reactivity of the hypervalent iodine reagent, we initially discovered a highly reactive trifluoromethylthiolating reagent, trifluoromethanesulfenate 1a. Structure-reactivity studies disclosed that the iodine atom of reagent 1a does not play an important role in this reagents reactivity. Consequently, a simplified second-generation electrophilic reagent, trifluoromethanesulfenate 1b, was developed. In parallel, we developed another shelf-stable, highly reactive electrophilic reagent with a broad substrate scope, N-trifluoromethylthiosaccharin (2). In this Account, we mainly describe our discovery of these two different types of electrophilic trifluoromethylthiolating reagents, trifluoromethanesulfenates 1a and 1b and N-trifluoromethylthiosaccharin 2. Systematic studies showed that both types of reagents are highly reactive toward a wide range of nucleophiles, yet the substrate scopes of these two different types of reagents are complementary. In particular, reagents 1a and 1b are more reliable in transition-metal-catalyzed reactions such as copper-catalyzed trifluoromethylthiolation of aryl/vinyl/alkylboronic acids and silver-catalyzed decarboxylative trifluoromethylthiolation of aliphatic carboxylic acids as well as in the organocatalytic asymmetric trifluoromethylthiolation of β-keto esters and oxindoles. Reagent 2 is more electrophilic than reagents 1a and 1b and is more efficient for direct trifluoromethylthiolation with nucleophiles such as alcohols, amines, thiols, and electron-rich arenes. The ease in preparation, broad scope, and mild reaction conditions make reagents 1a, 1b, and 2 very attractive as general reagents that allow rapid installation of the trifluoromethylthio group into small molecules.

Enantioselective Electrophilic Trifluoromethylthiolation of β-Ketoesters: A Case of Reactivity and Selectivity Bias for Organocatalysis†

A chiral Lewis base or a phase-transfer catalyst (PTC) can mediate the highly enantioselective trifluoromethylthiolation of β-ketoesters with the previously developed SCF3 reagent. Reactions of indanone-derived β-ketoesters occurred with high yield and excellent enantioselectivity with quinine as catalyst. Reactions of tetralone- or 1-benzosuberone-derived β-ketoesters occurred with moderate to good enantioselectivity with a quinine-derived PTC.

Palladium-Catalyzed Trifluoromethylthiolation of Aryl C–H Bonds

A method for monotrifluoromethylthiolation of arenes via palladium-catalyzed directed C-H bond activation was described. The reaction was compatible with a variety of functional groups. Initial mechanistic studies disclosed that the turnover limiting step of the catalytic cycle did not involve C-H activation.

Cooperative dual palladium/silver catalyst for direct difluoromethylation of aryl bromides and iodides

Difluoromethylated arenes are one of the privileged structural motifs that are important for fine tuning the biological properties of drug molecules. No general catalytic method exists for the formation of difluoromethylarenes. Previous methods for the preparation of difluoromethylarenes typically required harsh conditions, multiple steps or stoichiometric amount of catalysts. Here we report a cooperative dual palladium/silver catalyst system for direct difluoromethylation of aryl bromides and iodides under mild conditions. We develop the system by initial preparation of the putative intermediates in the dual-catalytic cycles, followed by studying the elemental steps to demonstrate the viability of the proposed cooperative catalytic cycle. The reaction is compatible with a variety of functional groups such as ester, amide, protected phenoxide, protected ketone, cyclopropyl, bromide and heteroaryl subunits such as pyrrole, benzothiazole, carbazole or pyridine.