Fluoroolefin-Amine Adduct Deoxofluorination
Fluoroolefin-amine adducts (FAAs) belong to a broader group of α,α-fluoroalkyl amino reagents (FAR). FAAs are widely used for the conversion of alcohols and acids into the corresponding alkyl or acyl fluorides. Fluoroolefin-amine adducts (FAAs) are one of the oldest group of organic fluorinating agents, which became very popular due to their availability, simple synthesis, and ability to convert alcohols and acids into alkyl and acyl fluorides. The application of the first representative of this group – adduct of chlorotrifluoroethylene and diethylamine (Yarovenko reagent) – as a reagent for conversion of alcohols into alkyl fluorides was reported in 1959 .
The chemistry of FAAs and FAR was previously overviewed. Detailed reports can be found in the following articles: synthesis and chemistry of Yarovenko reagent , Yarovenko and Ishikawa reagents , TFEDMA reagent , adducts of amines and 2-H-pentafluoropropene , and FAR reagents .
The synthesis of FAAs is straightforward and is based on the reaction of the corresponding secondary amine (linear, dimethyl or diethyl amines, or cyclic – pyrrolidine, piperidine, or morpholine) with the corresponding fluoroolefin. Due to high electrophilicity of double bond, the addition of amines to fluoroolefins proceeds under mild conditions and often in the absence of a solvent. Using this procedure, a variety of FAAs can be prepared, including adducts of chlorotrifluoroethylene and diethylamine (DEA) [1, 6] (Yarovenko reagent) and other amines , hexafluoropropene and DEA (Ishikawa reagent) [8, 9], dimethylamine (DMA) and tetrafluoroethylene (TFEDMA) [10, 11, 12], various amines with 2-H-pentafluoropropene , adducts of perfluoromethyl vinyl ether with DMA , DEA , and long-chain perfluorinated vinyl ethers various amines[16, 17, 18]. The synthetic procedure involves slow addition of fluoroolefin either into a solution of amine in inert organic solvent (THF, dioxane, ether etc.) or into pure amine at low temperature, leading to the corresponding FAAs in moderate to high yields. Typically, these reactions are exothermic and require careful temperature control of the reaction mixture. Due to high reactivity FAAs toward glass, preferred materials of construction for reactors are TeflonR, carbon or stainless steel, polyethylene, polypropylene, etc.
The composition of FAAs depends strongly on the structure of starting fluoroolefin and reaction conditions. For example, a reaction of liquefied dimethylamine with tetrafluoroethylene (TFE) leads exclusively to saturated adduct (HCF2CF2N(CH3)2, TFEDMA) in high yield , while the reaction TFE with DEA is slow at ambient temperature, requires heating, and leads to only moderate yield of adduct, due to substantial tar formation .
All known FAAs are liquids, which can be distilled either at atmospheric or preferably at reduced pressure, with boiling points varied from 33 °C/6 mm Hg (Yarovenko reagent) to 32 °C/127 mm Hg (TFEDMA . Most of FAAs are prepared under anhydrous conditions and used without additional purification. Due to high reactivity of FAA toward glass (especially at elevated temperature), it should be avoided as material of construction during preparation and purification of FAAs .
Although Ghosez reagents of general structure R(R′)C = CFNR2″ formally are products of amine reaction with R(R′)C = CF2 usually, they are prepared using a sequence involving a reaction of the corresponding amide with phosgene, treatment of the iminium chloride with base, which leads to R(R′)C = CClNR2″  and it’s conversion into R(R′)C = CFNR2″ by treatment with KF or CsF at elevated temperature .
Stability of FAA at ambient temperature varies, depending on the structure. For example, Yarovenko reagent (ClCFHCF2N(C2H5)2) is the least stable and has to be either stored refrigerated or used freshly prepared , while TFEDMA has unlimited shelf life at ambient temperature, if it is stored, in the absence of moisture, in the vessels made of steel or TeflonR.
Most of FAA’s fume being exposed to moist air, react violently with water and are not compatible with hydroxyl-containing solvents. It also should be pointed out that the majority of FAAs are potent producers of hydrogen fluoride and should be handled by trained personnel, using personal protective equipment recommended for handling hydrogen fluoride.
Deoxyfluorination of Alcohols
The ability of FAAs to replace hydroxyl group of alcohols by fluorine was first reported by Yarovenko and Raksha  for HClCFCF2N(C2H5)2 (Yarovenko reagent). This reagent gained popularity after several research groups [6, 22, 23, 24] demonstrated its utility for the conversion of various steroids  and certain alkaloids  into the corresponding fluorides. Yarovenko reagent was extensively used for fluorination of steroids, and a review by Sheppard and Sharts  has an excellent overview of these reactions. The yields of the corresponding fluorinated steroids can vary broadly, depending on the structure and reaction conditions.
The Ishikawa group demonstrated application of hexafluoropropene diethylamine adduct for conversion of alcohols and carboxylic acids into alkyl and acyl fluorides , and later this reagent was used for deoxyfluorination of fatty , terpene , and halogenated  alcohols, α-hydroxy esters , nitro alcohols , and monoesters of ethylene glycol .
Despite the fact that adduct of tetrafluoroethylene and dimethylamine (TFEDMA) was first prepared in the late 1950's [10, 32], it found application as fluorinating agent only recently. Similar to Yarovenko and Ishikawa reagents, this compound was demonstrated to be a potent reagent for the conversion of hydrocarbon and polyfluorinated alcohols into the corresponding alkyl fluorides .
At the beginning of this century, the Koroniak research group introduced adducts of various amines with 2-H-pentafluoropropene and studied their reaction of various alcohols , and reported data  suggest slightly lower reactivity of this reagent compared to Yarovenko, Ishikawa, or TFEDMA agents.
The influence of the ratio FAA to alcohol was studied in case of CF3CH = CFN(C2H5)2 (DEPFPA), and it was shown that the best yields in the reaction of (R)-(-)-2-octanol, cholesterol, and t-butanol can be achieved using excess of fluorinating agent (2:1 or 3:1 molar ratio of DEPFPA to alcohol) .
Fluorination of Alcohols
In most cases, deoxyfluorination of primary alcohols is carried out at elevated temperature (40–65 °C), optionally, in inert solvent, such as HCCl3, CH2Cl2, ether, etc. While the isolation of the products is not difficult in cases when column chromatography can be used (high boiling point or crystalline products), it can be problematic in case of materials with boiling points close to those of RfC(O)NR2 by-products. On lab scale, the product isolation is usually carried out by washing reaction mixture with water. It should be pointed out that this method is not very effective in case of Yarovenko and Ishikawa reagents, due to high partion coefficient of amides in organic phase. TFEDMA reagent offers some advantage, since HCF2C(O)N(CH3)2 has significantly higher solubility in water .
It also should be pointed out that a drawback of Yarovenko reagent is the formation of chlorine-containing by-products during fluorination process, especially at elevated temperatures . Chlorine in this case derives from the decomposition of the reagent resulting in the formation of chlorinated impurities, which sometime may be significant .
Ghosez-type reagents offer certain advantages. Since this reagents do not produce additional amount of HF in reaction with alcohols, deoxyfluorination reaction proceeds under neutral conditions, which allows to achieve higher selectivity in case of acid-sensitive materials . Additional examples of fluorination reactions using (CH3)2C = CFN(i-Pr)2 can be found in ref. [5, 36].
Secondary and Tertiary Alcohols
Secondary alcohols are more reactive toward FAAs. The fluorination reaction usually proceeds under milder condition (0–20 °C) and leads to the formation of secondary alkyl fluorides. Yields of fluorides are lower (typically 40–70%), due to olefin by-product formation as a result of competitive dehydration process.
Fluorination of optically active alcohols by FAAs usually proceeds with inversion of configuration, with ee's varying between 40% and 99%. For example, the reaction of R-(-)-octanol-2 and DEPFPA proceeds with complete inversion leading to pure S-(+)-2-fluorooctane in yields up to 85% , while fluorination of S-(+)-octanol-2 using Yarovenko reagents resulted in the formation of 2-fluorooctane with ~88% optical purity (40% yield, 78:22 mixture of F-octane/octenes) .
Cyclic alcohols react with FFAs under mild conditions (as low as −25 °C), and the result of reaction strongly depends on the size of cycle of alcohol and type of fluorinating agent. In case of TFEDMA, fluorination of cyclopentanol and cycloheptanol leads the corresponding fluorides as predominate products (ratio fluoride/olefin 78:22 in both cases), while cyclooctanol gives the predominantly cyclooctyl fluoride (ratio fluoride/olefin 55:45). Cyclohexene forms as a major product in case of cyclohexanol and TFEDMA reaction (ratio fluoride/olefin 9:91) , while in case of Ishikawa reagent, cyclohexene was reported to be a single product . On the other hand, (CH3)2C = CFN(i-Pr)2 was reported to convert cyclopentanol selectively into the corresponding fluoride (86% yield) . The absence of significant amount of cyclopentene in this case may be attributed to the absence of hydrogen fluoride in the system, which can promote dehydration of alcohol.
Allylic and Propargylic Alcohols
Allenes in this case form as a result of Claisen-type rearrangement involving intermediate “A” (Eq. 7) . Similar reaction leading to the corresponding unsaturated fluorinated amides was also reported for the reaction of Ishikawa reagent  and [(C2H5)2NCF = CHCF3, DEPFPA]  with allylic alcohols, as a result of Eschenmoser-Claisen-type rearrangement.
Benzylic Alcohols and α-Hydroxy Carbonyl Compounds
1-Phenylethanol produces 1-fluoro-1-phenylethane in reaction with Ishikawa or Yarovenko reagents  in 50% yield. Fluorination of optically active 1-phenylethanol (using Yarovenko reagent) was shown to proceed with inversion, leading to the corresponding stereoisomer with 55% ee . Detailed summary on fluorination of various benzylic alcohols using Yarovenko and Ishikawa reagents can be found in Ref. .
It should be pointed out that these reactions are extremely selective toward hydroxyl, while carbonyl group in all cases stays intact.
Fluorination of optically active α-hydroxy carbonyl compounds by FAAs proceeds in stereoselective fashion with inversion at stereocenter. Typically ees in this reactions are in a range 55–80%  for reactions of Yarovenko and Ishikawa reagents with optically active ethyl mandelate  and 26% for reaction of TFFEDMA and methyl mandelate ; TFEDMA was reported to convert optically active derivatives of proline into the corresponding fluorides in 85% ee , but much higher ee (up to 97%) was reported recently for the fluorination of pure enantiomers of lactic acid esters using TFEDMA .
Fluorination of Steroids and Natural Products
FAAs are widely used for regio- and stereoselective fluorination of various steroids. For example, 5-cholestane-3-ol (cholesterol) was converted into the corresponding fluoride in 72–83% yield using Yarovenko and Ishikawa reagents , TFEDMA , or adducts of 2-H-pentafluoropropene and amines . Independent of the reagent, the fluorination of cholesterol is completely stereoselective and proceeds with complete inversion at stereocenter leading to 3-β-fluorocholest-5-ene in 72–83% yield. In case of other steroids, yields of fluorinated products may vary broadly, depending mostly on the structure of starting steroid, while the nature of fluorinating agent seems to be less important. A comprehensive summary on the use of Yarovenko and Ishikawa reagents for the synthesis of fluorinated steroids can be found in review articles [1, 2].
FAAs in general are not active toward ring-bonded hydroxyls of carbohydrates; however, side chain –OH group can be replaced by fluorine .
Successful fluorination of gibberellins, kaurenoids, and brefeldin A leading to the corresponding fluoro derivatives was reported for Yarovenko reagent. Ishikawa reagents was used for the replacement of side chain OH group in some β-lactams and for preparation of antibacterial agent florfenicol .
Carbonyl Compounds and Acids
In general, FAAs are less potent fluorinating agents compared to sulfur tetrafluoride or DAST and would not convert C = O group into –CF2-. While the reaction of TFEDMA with propionic aldehyde at 100 °C was reported to give C2H5CF2H in moderate yield and selectivity , neither adamantanone-2 or ethyl pyruvate produced the corresponding difluorides under similar conditions  .
On the other hand, β-diketones were found to be active toward TFEDMA producing selectively RC(O)CH2CF2R (R = CH3, C2H5, C3H7) in 42–63% yield at elevated temperature. Two-step mechanism of this process involves the interaction of enolic form of β-diketone with TFEDMA leading to the formation of RC(O)CH = CFR and a mole of HF in first step, followed by the addition of HF across the double bond of RC(O)CH = CFR, leading to the corresponding difluoride . It should be pointed out that this reaction is applicable to noncyclic, aliphatic β-diketones, since in case of cyclic β-diketones the reaction results in exclusive formation of cyclic β-diketones carrying difluoroacetyl group in 2-position .
FFAs are useful reagents for one-step conversion of acids into acyl fluorides. Ishikawa and Yarovenko reagents  and TFEDMA  can be used for the conversion of aliphatic, aromatic, and sulfonic acids into acyl (sulfonyl) fluorides in moderate to high yields. One disadvantage of this process, a formation of acidic impurities (HF), can be overcome by carrying out the reaction in the presence of NaF . In this case the process leads to the formation of pure, HF-free acyl fluorides.
Mechanism of Deoxyfluorination Reaction
The mechanism involving cyclic transition state does explain the preferential formation of product with inverted stereochemistry in case of optically active alcohols and relatively high stereoselectivity of fluorination, since in this case the nucleophilic attack of fluoride anion on carbon will occur preferential from less hindered side. The formation of olefin by-products, especially in case of secondary and tertiary alcohols, may be a result of competitive process involving the formation of carbocation intermediate. However, in some cases, the formation of olefin may proceed without the formation of carbocation, since, in the reaction of TFEDMA with HCF2CF2C(CH3)2OH (toluene solvent, 100 °C), the formation of products of toluene alkylation was not observed, as it would be expected in case of the process involving the formation of free carbocation .
- 1.C.M. Sharts, Sheppard, W.A, Org. Reactions 21 (1974), pp. 158–173 and references herein.Google Scholar
- 2.S. Bohm, “Yarovenko and Ishikawa Reagents” in: Methods of Organic Chemistry (Houben Weyl), ed B. Basner, Hagemann, H., Tatlow J.C. (New York, 2000),v. E10b/1, pp. 99–112 and references herein.Google Scholar
- 3.C.P. Junk, V.A. Petrov, “1,1,2,2-Tetrafluorethyl-N,N-Dimethylamine” in e-EROS Encyclopedia of Reagents for Organic Synthesis (John Wiley & Sons, Ltd., 2014), pp. 1–2Google Scholar
- 4.J. Walkowiak, H. Koroniak, “Preparation of α-Fluoro Amino and α-Fluoro Enamino Reagents” in: Efficient Preparation of Fluorine Compounds, ed. H.W. Roesky (J.Wiley & Sons Inc., 2013), Chpt. 58, pp. 379–384.Google Scholar
- 5.V.A. Petrov, α,α-Fluoroalkyl(alkenyl) amino reagents (FAR) – recent development, Adv. Org. Synth. 2 (2006) 269–290 and references hereinGoogle Scholar
- 6.N.N. Yarovenko, M.A. Raksha, Fluorination with α-fluorinated amines, Zh. Obshch. Khim. 29 (1959) 2159–2163.Google Scholar
- 7.D.E. Ayer, (to DuPont) US Pat. 3,153,644 (1964).Google Scholar
- 8.I.L. Knunyants, L.S. German, B.L. Dyatkin, Addition reactions of perfluoroölefins. VI. Reaction of perfluoroisobutylene and perfluoropropylene with nucleophilic reagents, Izv. Akad. Nauk SSSR, Ser. Khim. (1956) 1353–1360.Google Scholar
- 9.A. Takaoka, H. Iwakiri, N. Fujiwara, N. Ishikawa, Use of hexafluoropropene and dialkylamine adducts as fluorinating agents for alcohols and carboxylic acids. Synthesis of tetrafluoropropionamidines, tetrafluoroethyl-substituted benzo heterocycles, and fluorocytosine derivatives, Nippon Kagaku Kaishi (1985) 2161–2168.Google Scholar
- 10.D.C. England, L.R. Melby, M.A. Dietrich, R.V. Lindsey, Jr., Nucleophilic reactions of fluoroölefins, J. Am. Chem. Soc. 82 (1960) 5116–5122.Google Scholar
- 11.V.A. Petrov, W. Hong, W.C. Petersen, S. Swearingen, 1,1,2,2-Tetrafluoroethyl-N,N-dimethylamine: a new selective fluorinating agent, Fluorinated Bioact. Compd. Agric. Med. Fields, Proc. Conf. (1999) 18/11–18/13.Google Scholar
- 18.G.G. Furin, I.A. Salmanov, V.G. Kiriyanov, Reaction of 1,1,2-trifluoro-2-[hexafluoro-2-(heptafluoropropoxy)propoxy]ethene with some amines, Zh. Prikl. Khim. 72 (1999) 1345–1353.Google Scholar
- 21.A. Colens, Demuylder, M., Téchy, B., Ghosez, L., Nouveau J. Chim., 1 (1977) 369.Google Scholar
- 25.D.E. Ayer, Tetrahedron Lett. (1962) 1065.Google Scholar
- 27.S. Watanabe, T. Fujita, K. Suga, I. Nasuno, T. Kuramochi, Fluorination of various terpenic alcohols and fatty alcohols with N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine, Yukagaku 33 (1984) 58–60.Google Scholar
- 32.N.N. Yarovenko, Raksha M.A., Shemanina V.N, Vasilyeva, A.S, J. Gen. Chem USSR, Engl.Transl., 27 (1957).Google Scholar
- 33.C.P. Junk, V.A. Petrov, (E. I. du Pont de Nemours and Company, USA. 2009).Google Scholar
- 36.P. Kirsch, in: Modern Fluoroorganic Chemistry, (Wiley-VCH, 2009).Google Scholar
- 38.V. Dedek, Liska, F., Chem. Commun. (Cambridge) 32 (1967) 4297.Google Scholar
- 40.J. Kopecky, Smejkal, J., J. Chem. Ind. (1969) 271.Google Scholar
- 42.M.A. K. Ogu, K. Ogura,, Allylic alcohols Ishikawa, Tetraherdron Lett. (1998) 305–308.Google Scholar
- 45.N. Lui, S. Pazenok, (Bayer CropScience AG, Germany). WO 2008049531, 2008.Google Scholar