Ni-Catalyzed Reductive Cross-Coupling of Cyclopropylamines and Other Strained Ring NHP Esters with (Hetero)Aryl Halides

Abstract

A nickel-catalyzed reductive cross-coupling of cyclopropylamine NHP esters with (hetero)aryl halides is reported. This efficient protocol provides direct access to 1-arylcyclopropylamines, a bioisosteric motif commonly used in small molecule drug discovery. The reaction proceeds rapidly (<2 h) with excellent functional group tolerance and without requiring heat-or airsensitive reagents. The method can also be extended to the arylation of four-membered strained rings. The NHP esters are easily obtained from the corresponding commercially available carboxylic acids in one step with high yields and no column chromatography.

Unlocking Tertiary Acids for Metallaphotoredox C(sp2)–C(sp3) Decarboxylative Cross-Couplings

“…Highly functionalized scaffolds were also explored, providing low but isolable yields of products derived from pharmacologically relevant aryl halides ( 52–54 ) − and demonstrating the viability of this reaction for late-stage functionalization of bioactive compounds. Substrate limitations for this method include linear acids without pendant carbamates ( 55 ), a cyclopropane substrate ( 56 ), α-hydroxy acids ( 57 ), and acids with increased steric bulk ( 58 ); aryl halide limitations include ortho -substitution ( 59 ), monocyclic heteroarenes ( 60 ), and electron-rich aryl bromides ( 61 )…”

Decarboxylative, Radical C–C Bond Formation with Alkyl or Aryl Carboxylic Acids: Recent Advances

“…Using a zinc-packed bed, the reaction could also be scaled up in continuous flow with a 45 min residence time (Figure 5). Similar decarboxylative XEC reactions with strained carbo-or heterocycles have also recently been described, including for cyclopropylamine 32 and azetidine 33 NHPI esters, greatly expanding the 3D chemical space that is accessible using XEC reactions.…”

Decarboxylative Cross-Electrophile Coupling of (Hetero)Aromatic Bromides and NHP Esters

“…1 H NMR (CD 3 OD, 600 MHz) δ 8.00 (s, 1H), 7.68 (d, 1H, J = 8.4 Hz), 7.46 (s, 1H), 7.12 (d, 1H, J = 8.4 Hz), 5.83 (dd, 1H, J = 9.9, 2.2 Hz), 4.00−4.04 (m, 1H), 3.85 (td, 1H, J = 11.3, 2.9 Hz), 2.48−2.54 (m, 1H), 2. 33 2-Phenyl-5-(tetrahydrofuran-3-yl)pyridine (15). The product was prepared using the general procedure using 24 mol % L3 and nickel(II) chloride•glyme, 1.3 equivalents of the NHP ester, 1.2 equivalents of TBAI, and 12 equivalents zinc.…”

“…However, even while employing these tactics, the yields for many couplings involving aryl bromides remained modest, and this report was limited to the use of strained tertiary NHP esters. Recently, additional reports describing the use of (hetero)aryl bromides in the reductive cross-coupling of NHP esters have been published, but they are either limited to a class of strained tertiary NHP esters 15 or utilize electrochemistry as the terminal reductant. 16 ■…”