Good Partnership between Sulfur and Fluorine: Sulfur-Based Fluorination and Fluoroalkylation Reagents for Organic Synthesis

Ni, Chuanfa; Hu, Mingyou; Hu, Jinbo

doi:10.1021/cr5002386

Cited by 1,097 publications

(381 citation statements)

References 593 publications

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“…Such structures also serve to combat the continued challenge of narrowing intellectual property (IP) space (1). These motifs can be rather unusual in that they are often not found in natural products: fluoroalkyl groups (2, 3) and strained ring systems including small spirocycles and bicycles are examples (4). Interest in the latter area was fueled by an ongoing program at Pfizer (5), where difficulties in the synthesis of bicyclo[1.1.1]pentan-1-amine ( 2 , Fig.…”

mentioning

confidence: 99%

Strain-release amination

Gianatassio

Lopchuk

Wang

et al. 2016

Science

406

254

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To optimize drug candidates, modern medicinal chemists are increasingly turning to an unconventional structural motif: small, strained ring systems. However, the difficulty of introducing substituents such as bicyclo[1.1.1]pentanes, azetidines, or cyclobutanes often outweighs the challenge of synthesizing the parent scaffold itself. Thus, there is an urgent need for general methods to rapidly and directly append such groups onto core scaffolds. Here we report a general strategy to harness the embedded potential energy of effectively spring-loaded C–C and C–N bonds with the most oft-encountered nucleophiles in pharmaceutical chemistry, amines. Strain release amination can diversify a range of substrates with a multitude of desirable bioisosteres at both the early and late-stages of a synthesis. The technique has also been applied to peptide labeling and bioconjugation.

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confidence: 99%

Strain-release amination

Gianatassio

Lopchuk

Wang

et al. 2016

Science

406

254

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“…[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] There is, however, few examples for the introduction of the longer-chain perfluoroalkyl moieties, such as the C 2 F 5 group, into organic molecules (Scheme 2). 36,37,38 For instance, Hartwig and coworkers successfully employed stable (phen)Cu(C 2 F 5 ), prepared from reaction of CuOt-Bu with C 2 F 5 SiMe 3 , for pentafluoroethylation of arylboronate esters and heteroaryl bromides.…”

Section: Scheme 1 Bioactive Compounds Containing Perfluoroalkyl Groupsmentioning

confidence: 99%

A class of effective decarboxylative perfluoroalkylating reagents: [(phen)₂Cu](O₂CR_F)

et al. 2016

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“…Trifluoromethyl containing motifs in an aromatic system are common pharmacophores (Fig. 1)1224252627282930 and there is a great current interest in the discovery of trifluoromethylation methods upon electrophilic and radical trifluoromethylations of arenes and heteroarenes as a consequence of advances in catalysis3456789, and new trifluoromethylating reagents and methods678910111213. Such growth based on the late-stage introduction of a trifluoromethyl group onto a aryl ring is in stark contrast to the synthetic applications of trifluoromethyltrimethylsilane (TMSCF 3 , also known as Ruppert−Prakash reagent)1415, as notably less toxic, relatively cheaper, and widely accepted nucleophilc trifluoromethylating reagent, in the synthesis of trifluoromethylated arenes based on the pre-introduction of a trifluoromethyl group onto a “aromatic to be” substrate12345678910111213141516171819.…”

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confidence: 99%

4-Trifluoromethyl-p-quinols as dielectrophiles: three-component, double nucleophilic addition/aromatization reactions

Dong

Shi

Pan

et al. 2016

Sci Rep

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In recent years, numerous methods have emerged for the synthesis of trifluoromethylated arenes based on the late-stage introduction of a trifluoromethyl group onto an aryl ring. In sharp comparison, the synthesis of trifluoromethylated arenes based on the pre-introduction of a trifluoromethyl group onto an “aromatic to be” carbon has rarely been addressed. It has been found that 4-trifluoromethyl-p-quinol silyl ethers, the readily available and relatively stable compounds, can act as dielectrophiles to be applied to multi-component reactions for the synthesis of various trifluoromethylated arenes. Catalyzed by In(OTf)3, 4-trifluoromethyl-p-quinol silyl ethers react with C-, N-, and S-nucleophiles, respectively, in a regiospecific 1,2-addition manner to generate the corresponding highly reactive electrophilic intermediates. Further reaction of the in-situ generated electrophiles with a C-nucleophile followed by spontaneous aromatization enables the construction of functionalized trifluoromethyl arenes. This three-component, double nucleophilic addition/aromatization reaction based on the pre-introduction of a trifluoromethyl group onto an “aromatic to be” carbon provides a divergent strategy for the synthesis of trifluoromethylated arenes under mild reaction conditions in a single operation.

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Good Partnership between Sulfur and Fluorine: Sulfur-Based Fluorination and Fluoroalkylation Reagents for Organic Synthesis

Cited by 1,097 publications

References 593 publications

Strain-release amination

Strain-release amination

A class of effective decarboxylative perfluoroalkylating reagents: [(phen)₂Cu](O₂CR_F)

4-Trifluoromethyl-p-quinols as dielectrophiles: three-component, double nucleophilic addition/aromatization reactions

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Good Partnership between Sulfur and Fluorine: Sulfur-Based Fluorination and Fluoroalkylation Reagents for Organic Synthesis

Cited by 1,097 publications

References 593 publications

Strain-release amination

Strain-release amination

A class of effective decarboxylative perfluoroalkylating reagents: [(phen)2Cu](O2CRF)

4-Trifluoromethyl-p-quinols as dielectrophiles: three-component, double nucleophilic addition/aromatization reactions

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Product

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A class of effective decarboxylative perfluoroalkylating reagents: [(phen)₂Cu](O₂CR_F)