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Synthesis of fluoroalkanes, perfluoralkanes and related compounds


Recent Literature

A cooperative interplay of halogen- and hydrogen-atom transfer enables the synthesis of gem-difluoroalkanes from unactivated sp3 precursors. The method is characterized by its simplicity, generality, and site selectivity, including the functionalization of advanced intermediates and olefin feedstocks.
W.-J. Yue, C. S. Day, A. J. B. Rucisnski, R. Martin, Org. Lett., 2022, 24, 5109-5114.

Intermolecular addition of perfluoroalkyl radicals on electron rich alkenes and alkenes with electron withdrawing groups in water, mediated by silyl radicals gives perfluoroalkyl-substituted compounds in good yields. The radical triggering events employed consist of thermal decomposition of 1,1′-azobis(cyclohexanecarbonitrile) (ACCN) or dioxygen initiation.
S. Barata-Vallejo, A. Postigo, J. Org. Chem., 2010, 75, 6141-6148.

Pentafluoroethyl copper (CuC2F5), which can be synthesized from a cuprate reagent and ethyl pentafluoropropionate in quantitative yield, is an economical and useful pentafluoroethyl source. The reagent was successfully applied to two types of pentafluoroethylations with arylboronic acids and aryl bromides.
H. Serizawa, K. Aikawa, K. Mikami, Org. Lett., 2014, 16, 3456-3459.

H. Serizawa, K. Aikawa, K. Mikami, Org. Lett., 2014, 16, 3456-3459.

A palladium-catalyzed direct monofluoromethylation of arylboronic esters produces monofluoromethyl arenes at room temperature within 4 h with a good functional group tolerance. The monofluoromethylating agent, CH2FI, can readily be prepared via a halogen-exchange process.
J. Hu, B. Gao, L. Li, C. Ni, J. Hu, Org. Lett., 2015, 17, 3086-3089.

Tri(9-anthryl)borane catalyzes a visible-light-induced trifluoromethylation of unactivated alkenes with CF3I. The mild reaction conditions tolerate various functional groups, and the reaction could be extended to perfluoroalkylations with C3F7I and C4F9I.
J. Moon, Y. K. Moon, D. D. Park, S. Choi, Y. You, E. J. Cho, J. Org. Chem., 2019, 84, 12925-12932.

A simple and efficient 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-promoted Heck-type alkene perfluoroalkylation of alkenes with perfluoroalkyl iodides in good yields proceeds smoothly via a radical process under visible light irradiation in the absence of an additional photocatalyst in ethyl acetate as a green solvent. DBU acts as both a halogen bond acceptor and a base.
L. Tang, G. Lv, Y. Fu, X.-P. Chang, R. Cheng, L. Wang, Q. Zhou, J. Org. Chem., 2022, 87, 14763-14777.

The use of mesoporous graphitic carbon nitride (mpg-CN) as a recyclable, nontoxic, and heavy-metal-free photocatalyst enables an efficient, eco-friendly, and divergent perfluoroalkylation of terminal alkynes. Switching the reaction solvents provides libraries of perfluoroalkylated alkynes, alkenes, and alkenyl iodides to be synthesized in good yields.
X. Shi, T. Song, Q. Li, X. Guo, Y. Yang, Org. Lett., 2022, 24, 8724-8728.

An operationally simple Pd-catalyzed three component reaction involving terminal alkynes, boronic acids, and perfluoroalkyl iodides gives trisubstituted perfluoroalkenes in a highly regio- and stereocontrolled manner by simultaneous additions across the triple bond in a radical-mediated process. The reaction is broad in scope and tolerates many functional groups.
Z. Li, A. García-Domínguez, C. Nevado, J. Am. Chem. Soc., 2015, 137, 11610-11613.

A visible-light-induced perfluoroalkylation reaction of aryl acrylic acids uses perfluoroalkyl iodides as radical precursors and inexpensive eosin Y as a photocatalyst. The easy accessibility of perfluoroalkyl iodides and the broad substrate scope, mild conditions, and metal-free catalyst make this decarboxylative protocol applicable for the transformation of inexpensive raw materials to high-value chemicals.
M. Yu, K. Niu, Z. Wang, Y. Liu, Q. Wang, Org. Lett., 2022, 24, 7622-7626.

The use of catalytic amounts of phosphines and blue light irradiation enables an efficient metal-free, iodo perfluoroalkylation of olefins under mild conditions within short reaction times. The reaction presumably proceeds upon generation of perfluoroalkyl radicals, which are formed by catalyst-induced absorption enhancement.
L. Helmecke, M. Spittler, K. Baumgarten, C. Czekelius, Org. Lett., 2019, 21, 7804-7808.

A method for hydrofluoroalkylation of alkenes with trifluoroacetic esters under visible light irradiation affords difluorinated products using readily available trimethyltriazinane as a stoichiometric reducing agent. The cleavage of the C-F bond by a triazinane-derived radical involves a single electron reduction coupled with fluoride transfer.
V. S. Kostromitin, A. O. Sorokin, V. V. Levin, A. D. Dilman, Org. Lett., 2023, 25, 6598-6602.

A photochemically mediated defluorinative hydroalkylation of ethyl trifluoroacetate with a diverse suite of alkenes in the presence of sodium formate enables a concise synthetic approach to novel gem-difluoro analogs of FDA-approved pharmaceutical compounds. Furthermore, trifluoroacetamides can also be functionalized via synergistic Lewis acid/photochemical activation.
M. W. Campbell, V. C. Polites, S. Patel, J. E. Lipson, J. Majhi, G. A. Molander, J. Am. Chem. Soc., 2021, 143, 19648-19654.

Under mild irradiation conditions using violet light-emitting diodes, a catalytic amount of N-(4-mercaptophenyl)pivalamide promotes monoselective defluoroalkylation of trifluoroacetates with a variety of aliphatic alkenes in the presence of a formate salt to provide valuable α,α-difluoro substituted aliphatic carboxylate esters.
C. Liu, N. Shen, R. Shang, Synthesis, 2023, 55, 1401-1409.

The addition of (pentafluoroethyl)- and (heptafluoropropyl)lithium to Weinreb and morpholine amides led to polyfluoro ketones in high to quantitative yields in short reaction times. The methodology can provide inhibitors for various lipolytic enzymes, including phospholipase A2.
C. G. Kokotos, C. Baskakis, G. Kokotos, J. Org. Chem., 2008, 73, 8623-2626.

Alkoxide-induced nucleophilic pentafluoroethylation and trifluoromethylation of aldehydes, ketones, and imines using pentafluoroethyl phenyl sulfone and trifluoromethyl phenyl sulfone, respectively, have been successfully achieved.
G. K. S. Prakash, Y. Wang, R. Mogi, J. Hu, T. Mathew, G. A. Olah, Org. Lett., 2010, 12, 2932-2935.

G. K. S. Prakash, Y. Wang, R. Mogi, J. Hu, T. Mathew, G. A. Olah, Org. Lett., 2010, 12, 2932-2935.

A direct and straightforward nucleophilic fluoromethylation of organic compounds employs a very labile lithium fluorocarbenoid (LiCH2F) generated from commercially available fluoroiodomethane. The versatility of the strategy is showcased in reactions involving a plethora of electrophiles providing highly valuable chemicals such as fluoroalcohols, fluoroamines, and fluoromethylated oxygenated heterocycles in very good yields.
G. Parisi, M. Colella, S. Monticelli, G. Romanazzi, W. Holzer, T. Langer, L. Degennaro, V. Pace, R. Luisi, J. Am. Chem. Soc., 2017, 139, 13648-13651.

A kinetic-controlled photocatalyst-free visible-light-induced stereoselective synthesis of synthetically important α,α-gem-difluoro-Z-allyl esters was succeeded at room temperature in good yields and excellent Z-selectivity through a reductive radical ethoxycarbonyldifluoromethylation of terminal aryl alkynes with blue LED (465 nm)-excited Hantzsch ester.
J. Hao, W. Ding, Z. Zheng, L. Sun, J. Dong, M. Li, W. Wan, J. Org. Chem., 2022, 87, 13750-13756.

A method for the homologation of ketones with the CF2 fragment involves silylation, room-temperature difluorocyclopropanation of silyl enol ethers, and selective ring opening of cyclopropanes under acidic conditions. The whole three-step sequence is conveniently performed in one-pot.
M. D. Kosobokov, V. V. Levin, M. I. Struchkova, A. D. Dilman, Org. Lett., 2015, 17, 760-763.

An iridium photocatalyst enables the addition of fluorinated groups to nitrones using ascorbic acid as a stoichiometric reducing agent. Partially fluorinated alkyl iodides can also be effectively used. The resulting hydroxylamines can be readily converted to valuable fluorinated amines by reduction with zinc.
V. I. Supranovich, V. V. Levin, M. I. Struchkova, A. D. Dilman, Org. Lett., 2018, 20, 840-843.

The application of continuous flow technology enabled a controlled generation of difluorocarbene from TMSCF3 and a catalytic quantity of NaI. The in situ generated electrophilic carbene reacts smoothly with a broad range of alkenes and alkynes to provide the corresponding difluorocyclopropanes and difluorocyclopropenes within 10 min residence time at high reaction concentrations.
P. Rullière, P. Cyr, A. B. Charette, Org. Lett., 2016, 18, 1988-1991.

A MW-based protocol enables a rapid preparation of 1,1-difluorocyclopropanes, using fluorinated acetate salts. The new procedure is not only considerably faster than conventional methods, but it also employs easily removed, low boiling-point solvents and avoids the use of highly toxic or ozone-depleting substances.
D. M. Gill, N. McLay, M. J. Waring, C. T. Wilkinson, J. B. Sweeney, Synlett, 2014, 25, 1756-1758.

Sodium bromodifluoroacetate (BrCF2CO2Na) is an effective difluorocarbene source for high-yielding­ synthesis of gem-difluorocyclopropanes and gem-difluorocyclopropenes under mild conditions.
K. Oshiro, Y. Morimoto, H. Amii, Synthesis, 2010, 2080-2084.