Pd(II)-Catalyzed, Picolinamide-Aided γ-(sp2)-C–H Functionalization of Racemic and Enantiopure α-Methylbenzylamine and Phenylglycinol Scaffolds

Abstract

In this paper, we report the Pd(II)-catalyzed, picolinamide DG-aided sp2 γ-C-H functionalization and expansion of the library of enantiopure α-methylbenzylamine and phenylglycinol scaffolds. We have shown the synthesis of a wide range of racemic and enantiopure ortho-C-H arylated, alkylated, brominated and iodinated α-methylbenzylamine and phenylglycinol scaffolds. Various racemic and R and S (chiral) sp2 γ-C-H functionalized α-methylbenzylamine and phenylglycinol scaffolds were synthesized with good enantiopurities. Racemic and enantiopure α-methylbenzylamine and phenylglycinol derivatives are important building blocks in organic synthesis and medicinal chemistry. Accordingly, this work contributes to the expansion of the libraries of α-methylbenzylamine and phenylglycinol motifs and substrate scope development through the Pd(II)-catalyzed bidentate directing group picolinamide-aided site-selective C-H activation and functionalization method.

Pd‐Catalyzed Arylation and Benzylation of Tyrosine at the δ−C(sp2)−H and C(2) Positions: Expanding the Library of Unnatural Tyrosines

“…Next, we attempted the Pd(II)‐catalyzed C(2)−H benzylation of tyrosine substrate 4 a ‐(DL) with benzyl bromides to obtain the tyrosine‐based diarylmethane scaffolds. Accordingly, the C(2)−H benzylation of 4 a ‐(DL) was attempted using the ortho C−H benzylation conditions (reported by Daugulis, Jiang and used by us earlier) [17,18a,d] . Initially, we performed a few reactions to find suitable conditions for obtaining the C(2) benzylated tyrosine by using a substrate 4 ‐(DL), benzyl bromide (4 equiv) in the presence of the Pd(OAc) 2 catalyst and K 2 CO 3 and PivOH additives in toluene at 110 °C.…”

Construction of β‐Phenylalanine Derivatives through Pd‐Catalyzed, C(sp2)−H (ortho) Functionalization

“…The β ‐phenylalanine substrate 3 a ‐(RS) was treated with p ‐anisyl iodide ( 5 a ) in the presence of the Pd(OAc) 2 catalyst (10 mol %) and AgOAc additive in toluene or t‐ AmylOH or 1,2‐DCE at 80–110 °C for 48 h (under the conditions used by various groups including Daugulis, Chen, Jiang and our group) [3,7b,d,e,9a] . These reactions yielded the bis C(sp 2 )−H ( ortho ) arylated β ‐phenylalanine 7 a ‐(RS) (terphenyl type β ‐amino acid motif) in 55–65 % yield (entries 1–3, Table 1).…”

“…We then attempted the Pd(II)‐catalyzed, picolinamide‐assisted ortho C−H bromination, iodination and chlorination of β ‐phenylalanine substrates (Scheme 5). Accordingly, β ‐phenylalanine substrate 3 a ‐(RS) and para substituted β ‐phenylalanine substrates 3 b – d ‐(RS) were treated with NBS in the presence of the Pd(OAc) 2 catalyst in 1,2‐DCE at 110 °C for 48 h (under the reported conditions) [7e,9a] . These reactions afforded the corresponding bis C(sp 2 )−H ( ortho ) brominated β ‐phenylalanine derivatives 13 a – d ‐(RS) in 23–62 % yields.…”

Pd(II)‐Catalyzed, γ‐C(sp2)−H Alkoxylation in α‐Methylbenzylamine, Phenylglycinol, 3‐Amino‐3‐Phenylpropanol Toward Enantiopure Aryl Alkyl Ethers

“…All the yields reported are isolated yields and the yields are not optimized and sometimes there is marginal variation in yields and enantiomeric ratio for the corresponding racemic/enantiopure pairs, this is perhaps based on the collection of pure fractions from the column chromatography based on the TLC and also may be due to inadvertent handling/processing errors of samples. Starting materials used in this work to carry out the Pd(II)‐catalyzed γ ‐C(sp 2 )−H alkoxylation with alcohols are known in the literature (see the supporting information) [12h,i] …”

“…A literature survey on the Pd(II)‐catalyzed DG‐aided ortho γ ‐C(sp 2 )−H functionalization of enantiopure α ‐alkylbenzylamine derivatives revealed that limited examples of alkylation, alkynylation, carbonylative cyclization, etc have been documented [12] . Along this line, we recently reported the Pd(II)‐catalyzed picolinamide‐aided ortho ‐C−H arylation/alkylation/halogenation of racemic and enantiopure α ‐methylbenzylamine and phenylglycinol scaffolds involving C−C, C−Br and C−I bond‐forming reactions [12h,i] …”