Synthesis of tri(di)fluoroethylanilines via copper-catalyzed coupling reaction of tri(di)fluoroethylamine with (hetero)aromatic bromides

Abstract

A practical and efficient synthesis of fluoroalkylanilines has been achieved via the Ullmann type coupling of (hetero)aromatic bromides with tri(di)fluoroethylamine.

Nickel‐Catalyzed N‐Arylation of Fluoroalkylamines

“…In a complementary competition employing the heteroatom‐containing nucleophiles 2,2‐difluoroethylamine, furfurylamine, and 2‐aminopyridine with 1‐chloronaphthalene, preferential formation of the pyridine‐derived aniline product ( B ) over both the alkylamine ( A ) and the β‐fluoroalkylamine ( 1 d ) derivatives was noted. The 1 d : A ratio (1.3:1) indicated a modest preference for the fluorinated versus the non‐fluorinated alkylamine nucleophile (Figure 4 C), in contrast to competition studies reported by Hu and co‐workers focusing on Cu‐catalyzed C‐N cross‐coupling of an aryl bromide, whereby the alkylamine was preferred (3.1:1) over the β‐fluoroalkylamine [11] . The competitive formation of 1 d and A herein also contrasts the results of studies focusing on the AdBippyPhos/Pd system, in which p ‐toluidine and n ‐butylamine nucleophiles were cross‐coupled preferentially, with no conversion of the contending pentafluoropropylamine [10] .…”

“…The first copper‐catalyzed C‐N cross‐coupling of β‐fluoroalkylamines was disclosed by Hu and co‐workers in 2019 (Figure 1). [11] Although the use of an inexpensive and Earth‐abundant base‐metal Cu catalyst and K 2 CO 3 in this chemistry is attractive, [12] forcing reaction conditions (110–120 °C and 5–20 mol % Cu 2 O) were required, and only transformations of (hetero)aryl bromides were described.…”

Nickel‐Catalyzed N‐Arylation of Fluoroalkylamines

“…The 1 d:A ratio (1.3:1) indicated a modest preference for the fluorinated versus the nonfluorinated alkylamine nucleophile (Figure 4 C), in contrast to competition studies reported by Hu and co-workers focusing on Cu-catalyzed C-N cross-coupling of an aryl bromide, whereby the alkylamine was preferred (3.1:1) over the b-fluoroalkylamine. [11] The competitive formation of 1 d and A herein also contrasts the results of studies focusing on the AdBippyPhos/Pd system, in which p-toluidine and nbutylamine nucleophiles were cross-coupled preferentially, [f] For 2 d we were unable to obtain sufficient resolution of the racemate under a range of HPLC conditions so as to allow unequivocal determination of enantioretentivity when using enantioenriched amine.…”

“…The first coppercatalyzed C-N cross-coupling of b-fluoroalkylamines was disclosed by Hu and co-workers in 2019 (Figure 1). [11] Although the use of an inexpensive and Earth-abundant base-metal Cu catalyst and K 2 CO 3 in this chemistry is attractive, [12] forcing reaction conditions (110-120 8C and 5-20 mol % Cu 2 O) were required, and only transformations of (hetero)aryl bromides were described.…”

Recent Advances in Nonprecious Metal Catalysis

“…These types of fluoroalkyl fragments are valuable as they are frequently used in therapeutic agents to modulate pharmacological properties, and for the purpose of increasing metabolic stability. Hu and coworkers examined a number of Cu complexes reported for the coupling of primary amines with (hetero)­aryl halides and found that only the oxalamides had appreciable reactivity with the fluorinated alkylamines . The ligands examined included phenanthroline, proline, N , N -diethylsalicylamide, 8-hydroxyquinoline, pipecolinic acid, and a variety of Ma’s oxalamide derived ligands.…”