Design of Trifluoroalkenyl Iodonium Salts for a Hypervalency‐Aided Alkenylation–Cyclization Strategy: Metal‐Free Construction of Aziridine Rings

The synthesis of fluorinated compounds and their use as pharmaceutical ingredients or synthetic building blocks have been in the focus of chemical and medicinal research. However, the efficient synthesis of trifluoromethylated nitrogen heterocycles is sometimes challenging. Herein, we disclose a simple aziridination process that relies on the use of amines and novel alkenyl iodonium reagents for the synthesis of strained, trifluoromethylated heterocycles. With the utilization of a newly designed and bench‐stable but highly reactive hypervalent alkenyl iodonium species, these three‐membered‐ring heterocyclic compounds can be efficiently constructed from simple amines under mild conditions in the absence of transition‐metal catalysts. The special reactivity of the new trifluoropropenyl synthon towards nucleophilic centers could be exploited in more general cyclization and alkenylation reactions in the future.     

Trifluoromethylated amino alcohol as chiral auxiliary for highly diastereoselective and fast Simmons–Smith cyclopropanation of allylic amine

Three advantages of a trifluoromethylated amino alcohol auxiliary in the Simmons–Smith cyclopropanation of allylic amines are described. The trifluoromethylated amino alcohol auxiliary reduces unwanted side reactions induced by its acidic, and thus less nucleophilic, hydroxy group. The auxiliary accelerated the reaction rate by its electron-withdrawing effect, and promoted the reaction with excellent diastereoselectivity.     

Reaction of Thiocarbonyl Fluoride Generated from Difluorocarbene with Amines

The reaction of thiocarbonyl fluoride, generated from difluorocarbene, with various amines under mild conditions is described. Secondary amines, primary amines, and o ‐phenylenediamines are converted to thiocarbamoyl fluorides, isothiocyanates, and difluoromethylthiolated heterocycles, respectively. Thiocarbamoyl fluorides were further transformed into trifluoromethylated amines by using a one‐pot process. Thiocarbonyl fluoride is generated in situ and is rapidly fully converted in one pot under mild conditions; therefore, no special safety precautions are needed.     

Esters of 2-aryl-2-isocyanato-3,3,3-trifluoropropionic acid in cyclocondensation with amines

The hitherto unknown representatives of fluorinated isocyanates, esters of 2-aryl-2-isocyanato-3,3,3-trifluoropropionic acid, were prepared. The synthetic potential of these compounds for preparation of trifluoromethylated hydantoins by the reactions of cyclocondensation with primary amines was demonstrated.     

Asymmetric synthesis of either diastereomer of trifluoromethylated allylic amines by the selective reduction of trifluoromethyl alpha,beta-unsaturated N-tert-butanesulfinyl ketoimines

Regio- and diastereoselective reduction of chiral trifluoromethyl alpha,beta-unsaturated N-tert-butanesulfinyl ketoimines 1 was achieved by choosing appropriate reducing agent and either diastereomer of the corresponding trifluoromethylated allylic amines was obtained with good yield and excellent diastereoselectivity (up to >99:1 dr).     

Copper-catalyzed oxidative trifluoromethylation of benzylic sp C-H bond adjacent to nitrogen in amines

Copper-catalyzed trifluoromethylation via oxidative sp³ C-H activation at the α-position of nitrogen in tetrahydroisoquinoline derivatives using DDQ and Ruppert-Prakash reagent has been successfully achieved. The reaction of various amines gave the corresponding trifluoromethylated products in 15-90% yields under mild conditions.     

Copper‐Promoted Conversion of Aromatic Amines into Trifluoromethylated Arenes: One‐Pot Sandmeyer Trifluoromethylation

A simple copper‐promoted one‐pot Sandmeyer trifluoromethylation of aromatic amines with Langlois’ reagent has been demonstrated. The reaction is performed in mild reaction conditions under an air atmosphere with good substrate scope and functional group compatibility. It provides an alternative and straightforward synthetic approach to access a variety of trifluoromethylated arenes.     

Asymmetric synthesis of trifluoromethylated allylic amines using alpha,beta-unsaturated N-tert-butanesulfinimines

[reaction: see text]. The trifluoromethide ion generated in situ from TMSCF(3) and TBAT (tetrabutylammonium triphenyldifluorosilicate), as well as TMAF (tetramethylammonium fluoride), adds to the alpha,beta-unsaturated N-tert-butanesulfinimines exclusively in a 1,2 fashion with high diastereoselectivities, affording the first examples of chiral trifluoromethylated allylic amines.     

Highly Enantioselective Aza‐Michael Reaction between Alkyl Amines and β‐Trifluoromethyl β‐Aryl Nitroolefins

The aza‐Michael addition reaction is a vital transformation for the synthesis of functionalized chiral amines. Despite intensive research, enantioselective aza‐Michael reactions with alkyl amines as the nitrogen donor have not been successful. We report the use of chiral N‐heterocyclic carbenes (NHCs) as noncovalent organocatalysts to promote a highly selective aza‐Michael reaction between primary alkyl amines and β‐trifluoromethyl β‐aryl nitroolefins. In contrast to classical conjugate‐addition reactions, a strategy of HOMO‐raising activation was used. Chiral trifluoromethylated amines were synthesized in high yield (up to 99 %) with excellent enantioselectivity (up to 98 % ee).     

Facile preparation of difluoromethyl- and monofluoromethyl-containing amides via Ritter reaction

Both secondary and tertiary difluoromethylated carbinols were found to readily react with acetonitrile under the catalysis of concentrated sulfuric acid to give the corresponding difluoromethylated acetamides in good yields, which is remarkably more efficient than the previously reported Ritter reactions with corresponding trifluoromethylated carbinols. Similarly, monofluoromethylated and (benzenesulfonyl)difluoromethylated carbinols have shown good reactivity in the Ritter reactions. Since the acetamides can be mildly deacetylated to give amines, the present methodology provides a convenient way for the synthesis of both difluoromethyl- and monofluoromethyl-containing amines starting from simple carbonyl compounds.     

Synthesis of trifluoromethylated amines using 1,1-bis(dimethylamino)-2,2,2-trifluoroethane

Lewis acid-catalyzed deamination of aminal, 1,1-bis(dimethylamino)-2,2,2-trifluoroethane, using ZnI2 in ether, generates the 2,2,2-trifluoro-1,1-dimethylaminoethyl carbocation, which undergoes synthetically useful electrophilic reactions with alkynes, a variety of electron-rich alkenes, and TMS cyanide to form trifluoromethylated alkynylamines, homoallylic amines, alpha,beta-unsaturated ketones, and cyanoamines in fair to good yields.     

Trifluoromethylation of non-activated aldimines with trimethyl(trifluoromethyl)silane in the presence of tetramethylammonium fluoride: A closer look into the reaction route

The reactions of non-activated aldimines with trimethyl(trifluoromethyl)silane and 1 equiv. of tetramethylammonium fluoride proceed via the formation of tetramethylammonium amides which were identified by low-temperature ¹⁹F NMR experiments. Consecutive reactions of the salts formed in situ with electrophiles yielded trifluoromethylated amines. Fluoride elimination is observed in the absence of electrophilic substrates leading to the formation of difluoromethylated ketimines.     

A powerful cascade approach for expeditious synthesis of trifluoromethylated furans

A powerful approach to synthesize trifluoromethylated furans has been developed. The method is operationally simple, broad in substrate scope, and amenable to scale-up using trifluoroacetic anhydride. Meanwhile, the strategy not only provided a versatile approach to synthesize trifluoromethylated furans but also provides a new method for exploring the new reactivity of trifluoroacetic anhydride.     

Enantio‐ and Diastereoselective Formal Hetero‐Diels–Alder Reactions of Trifluoromethylated Enones Catalyzed by Chiral Primary Amines

Enantioselective formal hetero‐Diels‐Alder reactions of trifluoromethylated enones and 2‐amino‐1,3‐butadienes generated in situ from aliphatic acyclic enones and chiral primary amines are reported. The corresponding tetrahydropyran‐4‐ones are formed in up to 94 % yield and with up to 94 % ee. The reaction was carried out through a stepwise mechanism, including initial aminocatalytic aldol condensation of 2‐amino‐1,3‐butadiene to the trifluoromethylated carbonyl group followed by an intramolecular oxa‐Michael addition. Both NMR investigation and theoretical calculations on the transition state indicate that the protonated tertiary amine could effectively activate the carbonyl group of the trifluoromethyl ketone to promote the addition process through hydrogen‐bonding interaction of N?H???F and N?H???O simultaneously, and thus provide a chiral environment for the approach of amino‐1,3‐butadienes to the activated trifluoromethyl ketone, resulting in high enantioselectivity.     

Efficient Synthesis of Trifluoromethyl Amines through a Formal Umpolung Strategy from the Bench‐Stable Precursor (Me4N)SCF3

Reported herein is the one‐pot synthesis of trifluoromethylated amines at room temperature using the bench‐stable (Me₄N)SCF₃ reagent and AgF. The method is rapid, operationally simple and highly selective. It proceeds via a formal umpolung reaction of the SCF₃ with the amine, giving quantitative formation of thiocarbamoyl fluoride intermediates within minutes that can readily be transformed to N‐CF₃. The mildness and high functional group tolerance render the method highly attractive for the late‐stage introduction of trifluoromethyl groups on amines, as demonstrated herein for a range of pharmaceutically relevant drug molecules.     

SYNTHESIS OF TRIFLUOROMETHYL-IMINES BY SOLID ACID/SUPERACID CATALYZED MICROWAVE ASSISTED APPROACH

A new solid acid/superacid catalyzed microwave assisted synthesis of trifluoromethyl-imines is described. Various α,α,α-trifluoromethylketones react readily with primary amines to produce the corresponding imines. Two different strategies have been employed; one is the application of microwave irradiation coupled with solvent-free solid acid catalysis. The other method, for highly deactivated substrates includes the use of a pressure vessel at 175 °C temperature, with solid superacid catalysis. Using the solid acid K-10 montmorillonite or the superacidic perfluorinated resinsulfonic acid Nafion-H, a wide variety of trifluoromethylated imines have been synthesized using the above methods. The products have been isolated in good to excellent yields and high selectivities. This new environmentally friendly synthetic methodology provides significantly higher yields than traditional methods during relatively short reaction times for the preparation of the target compounds.     

Visible-light mediated carbonyl trifluoromethylative amination as a practical method for the synthesis of β-trifluoromethyl tertiary alkylamines

We report the development of an operationally straigtforward, visible-light-mediated multicomponent strategy for the construction of β-trifluoromethylated tertiary alkylamines from feedstock aldehydes, secondary amines and a convenient source of trifluoromethyl iodide. The new process does not require a photocatalyst, is metal-free, displays a broad functional group tolerance and offers rapid, one-pot access to trifluoromethylated drug-like compounds that will be of interest in medicinal chemistry.

An operationally straightforward, visible-light-mediated multicomponent strategy for the construction of β-trifluoromethylated tertiary alkylamines from aldehydes, secondary amines and a convenient source of trifluoromethyl iodide is reported.     

Asymmetric Synthesis of Agrochemically Attractive Trifluoromethylated Dihydroazoles and Related Compounds under Organocatalysis

The unique, partially saturated, fluorinated five‐membered heterocyclic compounds, trifluoromethylated dihydroazoles, and their derivatives, have emerged as a new class of heterocycles with remarkable biological activities in the 21st century. Despite their small molecular structures, a single sterically demanding tetrasubstituted trifluoromethylated stereogenic carbon center has prevented chemists from achieving the asymmetric synthesis of these compounds. In this account, we describe our recent progress in the catalytic asymmetric synthesis of a series of trifluoromethylated heterocycles, such as isoxazolines and pyrrolines having a stereogenic carbon center, based on organocatalysis. Our protocols have advantages in terms of employing inexpensive reagents and organocatalysts and they would be useful for industrial production.     

Facile conversion of CF3-containing propargylic alcohol derivatives via the corresponding allenes

Empirical information on the acidity of the propargylic proton from our previous work allowed us to develop novel synthetic transformations of readily available terminally trifluoromethylated propargylic alcohols 1 into the corresponding allenyl tosylates 3a, 1-tosyloxy- or 1-acyloxy-4,4,4-trifluorobutan-2-ones 4, and 2-(2,2,2-trifluoroethyl)prop-2-en-1-ones 5, which was enabled by such common bases as NaOH and tertiary amines for affecting ready abstraction of this proton.     

Asymmetric synthesis of β-trifluoromethylated β-amino aldehyde as well as carboxylic acid derivatives using enantiopure α-trifluoromethylated homoallylamine

Asymmetric synthesis of β-trifluoromethylated β-amino aldehyde and acid derivatives via the oxidation of enantiopure α-trifluoromethylated homoallylamine as a new trifluoromethylated chiral building block is described.