Selective trifluoromethylthiolation of heteroaromatic sp2 C–H bonds with the 2nd generation of trifluoromethanesulfenamide reagent

“…In recent years, we have developed a new family of very stable reagents, namely the trifluoromethanesulfenamides ( 1 and 2 ), which have demonstrated their high efficiency in various electrophilic trifluoromethylthiolations 9a,b. 11 Consequently, their use in cross‐coupling reactions with boronic acids has been considered (Table 1).…”

Section: Trifluoromethylthiolation Of Biphenylboronic Acid (3 A)mentioning

confidence: 99%

Mild and Soft Catalyzed Trifluoromethylthiolation of Boronic Acids: The Crucial Role of Water

Glenadel

Alazet

Tlili

et al. 2015

Chemistry A European J

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The most reactive 2nd generation of trifluoromethanesulfenamides undergoes a copper-catalyzed cross-coupling reaction with boronic acids to afford CF3 S-molecules. Contrary to the previous methods in the literature, no base addition, no heating, and no large excess of reagents are required to obtain good results. Furthermore, a crucial role of a small amount of water to favor this reaction has been demonstrated. This constitutes the mildest described conditions for such a reaction.

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“…同时, 他们也发现, 在合成该苯胺骨架的试剂过程中, 当底物的胺含有吸电子取代基时会优先生成一个亚胺中间体, 该中间体可以在三氟乙酸的水解下, 进一步生成活性更高的第二代 Billard 试剂 [64] . 在 2014 年, 他们对该类试剂的反应活性进行了报道, 发现该类试剂相比第一代苯胺结构的试剂有着更为出色的反应活性, 除去上述报道的反应外还可以实现活泼 C-H 键底物 [69] 、杂环底物 C-H 键底物 [70] 、硼酸底物 [71] 剂 [72] (S,O)、活泼卤化物(类卤化物)极性反转的三氟甲硫基化反应 [73] 、炔烃的单、双三氟甲硫基化反应 [74] 以及富电子芳烃、杂芳烃底物的 C-H 键三氟甲硫基化反应 [75] (Scheme 33). [79] 、吲哚 [80] 、苯并呋喃 [81] 、苯并噻吩 [81] 以及苯并吡喃类衍生物 [82] .…”

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Recent Progress on Direct Trifluoromethylthiolating Reagents and Methods

Zhang¹,

Lü²,

Shen³

2017

Acta Chim. Sinica

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With a significantly high Hansch's hydrophobicity parameter (π＝1.44), electron-withdrawing trifluoromethylthio group (CF 3 S-) has been considered as one of the most lipophilic substituents and privileged fragments that are able to improve drug molecules' pharmacokinetic and physicochemical properties such as lipophilicity and metabolic stability. It is well-known that incorporation of the trifluoromethylthio group into small molecules greatly enhances its ability to cross lipid membranes and in vivo absorpotion rate. In addition, the high electronegativity of the trifluoromethylthio group significantly improves the small molecule's stablity in acidic environments. Not surprisingly, the trifluoromethylthio group has been of special attention not only from the academia but also from pharmaceutical and agrochemical industry for their use in isostere-based drug design. Development of highly efficient methods for the introduction of the trifluoromethylthio group into small molecules, thereafter, has become a subject of recent focus in the field of organic chemistry. In the early 1960s, a few methods for the formation of trifluoromethylthioethers were reported, which typically involved halogen exchange of the trichloromethyl-substituted compounds and trifluoromethylation of thiolated substrates. However, the conditions of these methods were harsh and incompatible with many common functional groups. Since 2008, new reagents and methods that were able to efficiently incorporate the trifluoromethylthio group under mild conditions have emerged, that pave the way for the facile introduction of trifluoromethylthio group into site-specific positions of the target molecules. In this review, we will first briefly introduce the indirect strategies for trifluoromethylthiolation including halogen exchange and trifluoromethylation of thiolated substrates, and then focus on the direct trifluoromethylthiolation strategies including the transition metal-catalyzed trifluoromethylthiolation reactions, electrophilic trifluoromethylthiolation reactions with electrophilic trifluoromethylthiolating reagents and radical trifluoromethylthiolations. These methods represent the most straightforward and promising approaches for the incorporation of the trifluoromethylthio group into small molecules. At the end, we will discuss the remaining problems and challenges in this particular field.

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Selective trifluoromethylthiolation of heteroaromatic sp2 C–H bonds with the 2nd generation of trifluoromethanesulfenamide reagent

Cited by 43 publications

References 29 publications

First and second generation of trifluoromethanesulfenamide reagent: A trifluoromethylthiolating comparison

First and second generation of trifluoromethanesulfenamide reagent: A trifluoromethylthiolating comparison

Mild and Soft Catalyzed Trifluoromethylthiolation of Boronic Acids: The Crucial Role of Water

Recent Progress on Direct Trifluoromethylthiolating Reagents and Methods

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