2-Fluoro-2-Phosphatoacetic Acid Triethyl Ester (CAS 2356-16-3): Synthesis and Application of Fluorinated Horner Reagent with Full Analysis
1、 Product Overview
Triethyl 2-fluoro-2-phosphonoacetate (TEFPA) is an important fluorinated organic phosphorus reagent that occupies a unique position in the field of organic synthesis.
As a classic Horner Wadsworth Emmons (HWE) reagent, its greatest value lies in its ability to simultaneously introduce fluorine atoms and carbon carbon double bonds into the target molecule, a function that many non fluorinated reagents cannot achieve.
2、 Basic Product Information
1）Product Name: Triethyl 2-fluoro-2-phosphonoacetate
2）CAS NO.：2356-16-3
3）Molecular formula: C8H16FO5P
4）Molecular weight: 242.18
5）Structural formula:
6）Purity: ≥ 99%
7）Appearance: Colorless and transparent liquid
8）Boiling point: 75 ° C/0.01 mmHg; 200 °C / 16 mmHg
9）Density: 1.194 g/mL (25 ° C)
10）Refractive index: n ² ⁰/D 1.425
11）Flash point: 73 ° C
12）Product Manager Email:ada@coreychem.com
3、 Frequently Asked Questions (FAQ)
1）What is the difference between TEFPA and conventional Wittig or Still Gennari reagents?
Compared to traditional Wittig reagents, its phosphoryl group (- P (O) (OEt) ₂) endows the reagent with better stability and reaction controllability.
Compared with the Still Ennari reagent, the core advantage of TEFPA is that it introduces fluorine atoms while constructing double bonds – although the Still Ennari reagent can achieve Z-selectivity, the product does not contain fluorine. Therefore, when the target molecule requires a fluorinated olefin structure, TEFPA is an irreplaceable choice.
2）How to control the E/Z stereoselectivity when using TEFPA for HWE reaction?
The stereoselectivity of TEFPA can be regulated by reaction conditions and substrate types, providing high flexibility for synthesis. For ketone substrates, the E-type product can be obtained under the conditions of Sn (OPO ₂ CF ∝) ₂/N-ethylpyridine; For aldehyde substrates, the use of Mg (II) tends to generate Z-shaped products at low temperatures. The ability to achieve E/Z switching from a single reagent is a significant advantage that distinguishes TEFPA from other fluorinated reagents.
3）What are the synthetic routes for TEFPA? Which one is more suitable for laboratory preparation?
There are mainly two routes.
The classic reaction is Michaelis Arbuzov reaction – triethyl phosphite reacts with ethyl bromofluoroacetate under heating conditions (about 130 ° C), with a yield of about 92%. However, ethyl bromofluoroacetate is expensive and toxic.
Another route was developed by Patois and Savignac, starting from diethyl dibromofluoromethylphosphonic acid ester and using butyl lithium and ethyl chloroformate at low temperature (-78 ° C), with a yield of about 89-92%. This route avoids toxic bromofluoroacetate, but requires handling of low temperature conditions and butyl lithium.
4）Is TEFPA applied in the field of batteries?
Yes, there is. There is research on the preparation of flame retardant electrolyte for lithium-ion batteries using ethyl 2-fluoro-2-phosphonoate. Adding it as a flame retardant additive to existing electrolytes can improve the safety of batteries without significantly affecting their electrochemical performance. In addition, it has also been used in the study of flame retardant gel electrolytes by in-situ polymerization.
5）What issues should TEFPA pay attention to when storing?
TEFPA is sensitive to light, moisture, and air. It is recommended to store in a sealed place under inert gas protection (such as nitrogen or argon) and store in a cool and dark place. When using, try to avoid repeatedly opening the lid and exposing it to the air to prevent moisture absorption and deterioration.
4、 Application Cases
1）Synthesis of E-type α – fluoroacrylate pharmaceutical intermediates
In the development of antiviral and anticancer drugs, α – fluoroacrylate structural units often appear as key pharmacophores.
TEFPA is the preferred synthetic reagent in this scenario – using the optimized scheme reported by Volchkov et al. (2023) for HWE alkylation of ketone substrates, a purity of>98% of the E-isomer can be obtained, and the intermediate can be purified by crystallization without column chromatography separation. This advantage is particularly significant in large-scale preparation, which can significantly reduce solvent consumption and operating time.
2）Construction of Z-Fluoroalkene Dipeptide Mimics
In the design of peptide mimetics drugs, fluoroalkenes are often used as electron acceptors for amide bonds.
The uniqueness of TEFPA lies in its ability to efficiently construct Z-fluoroalkenes on aliphatic substrates through a series of reduction alkylation reactions (treating acyl fluorophosphate intermediates derived from TEFPA with NaBH ₄/EtOH). This strategy has been successfully applied to the total synthesis of Cbz Gly – PSI [(Z) – CFC] – Gly (a fluorinated alkene dipeptide analogue), providing a new pathway for obtaining non natural amino acid mimetics.
3）Preparation of End Fluorinated Ethylene by Process Scaling up
For industrial process chemistry, whether the purification step is suitable for scaling up is a key indicator for evaluating the feasibility of synthetic routes.
The HWE hydrolysis decarboxylation cascade strategy based on TEFPA can prepare di – and tri substituted end fluorinated ethylene through crystallization purification instead of column chromatography. This route has been validated in the synthesis of antibacterial and anti-inflammatory compounds, and its feasibility for scaling up has been demonstrated.
4）Synthesis of Fluorinated Retinoic Acid Compounds
Retinoic acid compounds are important anti-cancer and dermatological drugs.
Efficient synthesis of 4-fluorosubstituted retinoic acid analogues can be achieved through the HWE reaction between TEFPA and aromatic aldehydes. The introduction of fluorine atoms not only changes the electronic distribution of the molecule, but may also enhance its binding affinity with retinoic acid receptors (especially RAR – β subtypes), providing a rich tool molecule for the study of structure-activity relationships.
5）Agricultural chemicals – Fluorinated analogues of pyrethroids
In the field of agrochemicals, TEFPA is applied in the synthesis of fluorinated analogues of pyrethroid insecticides.
By introducing fluorine atoms into the side chains of olefins, the metabolic stability and insecticidal activity of compounds can be improved. In addition, it can also be used to synthesize fluorine-containing pheromone analogues and aldehyde components, providing new chemical tools for integrated pest management.
5、 Safety and Storage
1）Store in a cool, well ventilated area and keep the container sealed；
2）Sensitive to light, moisture, and air, it is recommended to store under inert gas protection (such as nitrogen or argon)；
3）Store away from light, recommended temperature below 15 ° C (some suppliers suggest -20 ° C)；
4）Store separately from strong oxidants and strong alkalis
6、Product Manager Information
Product Manager: Ada Wang
Email: ada@coreychem.com
