Diastereoselective Pd-Catalyzed C–H Arylation of Ferrocenylmethanamines with Arylboronic Acids or Pinacol Esters

Abstract

An efficient diastereoselective synthesis of planar chiral ferrocenes via Pd­(II)-catalyzed direct C–H activation with arylboronic acids or pinacol esters is presented. The reaction was performed under mild conditions using commercially available achiral or chiral amino acids as ligands. The best results were obtained with (R)-Boc-alanine, which yielded products in 27–83% yield with diastereoselectivities ranging from 5:1 to 20:1 (11 examples). Diastereoisomeric products can also be obtained using (S)-Boc-alanine as a ligand. Stereoinduction of the reaction was explained by density functional theory calculations of possible transition states.

Diastereoselective Double C−H Functionalization of Chiral Ferrocenes with Heteroaromatics

“…The absolute configurations of CÀ H activation products 3 are analogous with our previous work, where we have used the same catalytic system. [10] Furthermore, we have measured CD spectra for these derivatives (see Supporting Information), suggesting that the whole series of products 3 has the same configuration of the planar stereogenic unit. CD spectra of diastereomeric products (R,S p )-3 a and (R,R p )-3 a show that planar stereogenic moiety is the dominant element of chirality (Figure 1b).…”

“…Recently, we have described a practical diastereoselective synthesis of planar chiral ferrocenes by Pd(II)catalyzed direct CÀ H bond activation with aryl boronic acids or pinacol esters. [10] This method tolerated both electron-donating as well as electron-withdrawing groups on the phenyl ring of used aryl boronic acids. Unfortunately, heteroaromatic boronic acids or esters remained a severe bottleneck in the functionalization of Ugi amine (1).…”

Transition-Metal-Catalyzed C–H Arylation Using Organoboron Reagents

“…Later, Sebesta and co-workers investigated a diastereoselective synthesis of axially chiral aminoalkyl ferrocene exploiting commercially available MPAA (Scheme 38). 50 The study shared resemblance with Gao's method 43 and served as an extension of that with marginally improved efficiency. Observably, (R)-amino acid promoted (R)-ferrocene conversion to (R,Rp)-arylferrocene whereas (S)-amino acid as replacement produced inferior yields due to spatial influence 44 of the ligand.…”

“…In an extension of the work of You, Gu, and co-workers (Scheme 31), 43 in 2019 Sebesta and co-workers investigated the diastereoselective synthesis of axially chiral (1-aminoethyl)ferrocenes exploiting a commercially available MPAA (Scheme 38). 50 The best results were obtained with Pd(OAc) 2 as the catalyst, (R)-Boc-Ala-OH as the ligand with K 2 CO 3 and TBAB in DMAc in air at 60 °C. Using this procedure, (R)-(1-aminoethyl)ferrocenes were arylated using (R)-Boc-Ala-OH as the ligand to give the (R,R p )-arylferrocene product whereas the use of (S)-Boc-Ala-OH resulted in lower yields due to spatial influence 44 of the ligand.…”

Comparison of Diastereoselective ortho-Metalations and C–H ­Activations of Chiral Ferrocenes

“…In 2019 our group reported a synthesis of planar chiral ferrocenes via diastereoselective C–H activation catalyzed by Pd II /MPAA (monoprotected amino acid) using catalytic amounts of both reagents. 86 Ugi’s amine ( R )- 1 was used as a convenient and commercially available starting material for this transformation (Scheme 20 ). Substituted aryl boronic acids and/or pinacol esters of boronic acids were used for the preparation of various chiral ferrocenyl amines ( R , R p )- 47 in up to 83% yield in very high diastereomeric purities (up to 20:1 d.r.).…”