A Brief Review on the Synthesis of the N-CF3 Motif in Heterocycles
Abstract
:1. Introduction
2. Three-Membered Heterocycles
3. Four-Membered Heterocycles
4. Five-Membered Heterocycles
4.1. Nucleophilic Fluorination
4.1.1. Fluorine/Halogen Exchange
4.1.2. Oxidative Desulfurization and Fluorination
4.1.3. Cyclization Induced by Fluoride Ion
4.2. Cyclization Based on N-CF3 Starting Materials
4.2.1. [3+2] Cycloaddition
4.2.2. Other Cyclization
4.3. Electrophilic Trifluoromethylation
5. Six-Membered Heterocycles
5.1. Nucleophilic Trifluoromethylation
5.2. [4+2] Cycloaddition
5.3. Other Approaches
6. Seven- and Larger-Membered Heterocycles
7. Other Methods
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Structure | pH 1.0 [d] | pH 7.4 [d] | pH 10.0 [d] |
---|---|---|---|
19a | 0.2 | 0.4 | 0.3 |
20a | <0.6 | <0.6 | <0.6 |
21a | >72 | >72 | >72 |
22a | >72 | >72 | >72 |
23a | >72 | >72 | 71 |
24a | <1.3 | <0.8 | <0.5 |
Structure | Number | Log D7.4 [a] | Chrom- log D7.4 [a] | ePSA [b] [Å2] | Caco-2 Papp [c] [10−6 cm/s] | HLM [d] [L/min/mg] |
---|---|---|---|---|---|---|
19a R = CF3 | 1.6 (0.1) | 1.5 (0.1) | 82 (1) | nd [e] | nd [e] | |
19b R = CH3 | 0.6 (0.1) | 1.3 (0.1) | 81 (1) | nd [e] | nd [e] | |
20a R = CF3 | >4.0 | 4.9 (0.2) | 38 (2) | nd [e] | nd [e] | |
20c R = CH3 | 2.8 (0.1) | 3.3 (0.1) | 50 (1) | nd [e] | nd [e] | |
21a R = CF3 | 3.7 (0.1) | 3.3 (0.0) | 73 (1) | 61 (27) | 47 (11) | |
21b R = CH3 | 2.7 (0.1) | 2.2 (0.1) | 92 (1) | 72 (1) | 4.8 (1.9) | |
22a R = CF3 | 3.0 (0.1) | 3.3 (0.0) | 39 (2) | 58 (18) | 39 (18) | |
22b R = CH3 | 2.3 (0.0) | 1.5 (0.1) | 56 (1) | 72 (20) | 172 (41) | |
23a R = CF3 | 2.2 (0.1) | 2.2 (0.0) | 92 (1) | 12 (8) | <3.0 | |
23b R = CH3 | 0.6 (0.1) | <0.0 | 98 (0) | 2.4 (0.9) | <3.0 | |
24a R = CF3 | >4.0 | >5.3 | 67 (1) | nd [e] | nd [e] | |
24b R = CH3 | 2.7 (0.1) | 3.3 (0.1) | 73 (0) | nd [e] | nd [e] |
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Lei, Z.; Chang, W.; Guo, H.; Feng, J.; Zhang, Z. A Brief Review on the Synthesis of the N-CF3 Motif in Heterocycles. Molecules 2023, 28, 3012. https://doi.org/10.3390/molecules28073012
Lei Z, Chang W, Guo H, Feng J, Zhang Z. A Brief Review on the Synthesis of the N-CF3 Motif in Heterocycles. Molecules. 2023; 28(7):3012. https://doi.org/10.3390/molecules28073012
Chicago/Turabian StyleLei, Zizhen, Wenxu Chang, Hong Guo, Jiyao Feng, and Zhenhua Zhang. 2023. "A Brief Review on the Synthesis of the N-CF3 Motif in Heterocycles" Molecules 28, no. 7: 3012. https://doi.org/10.3390/molecules28073012