Palladium(II)‐Catalyzed Sp³/Sp²γ‐ and δ‐C‐H Functionalization of Aryl Amines using 5‐Methylisoxazole‐3‐Carboxamide as Directing Group

Abstract

A dual objective-based study comprising exploration of 5-methylisoxazole-3-carboxamide (MICA) as a directing group (DG) for the Pd(II)-catalyzed sp 3

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

“…The C(2)−H arylation of tyrosine substrate 4 f ‐(DL) possessing the quinoline‐2‐carboxamide DG [21a] yielded the bis C(2)−H arylated product 7 ab ‐(DL) in low yield (<10 %, Scheme 3). Then, we performed the C(2)−H arylation of tyrosine substrate 4 g ‐(DL) possessing the 5‐methylisoxazole‐3‐carboxamide DG [18e,21b] with 5 a . This reaction afforded the bis C(2)−H arylated tyrosine derivative 7 ac ‐(DL) in good yield (80 %, Scheme 3).…”

Pd-Catalyzed Remote δ-C(sp2)–H Functionalization in Phenylalaninol: Expanding the Library of Phenylalaninols

“…On the basis of published work and our earlier experience of using O -acetylated phenylglycinol possessing the picolinamide DG as substrate; 6` d e , 9b 13d 16 we attempted the C–H arylation reaction using the O -acetylated phenylalaninol substrate ( RS )- 3a possessing the picolinamide DG (Table 1 ). Along this line, we also assembled O -TBS phenylalaninol 17c substrate ( RS )- 3f possessing the picolinamide DG and performed the C–H arylation of ( RS )- 3f (Scheme 2 ).…”

“…Additionally, the structure of a representative bis δ-C–H ( ortho ) arylated product (phenylalaninol-based terphenyl derivative) ( RS )- 6g was unequivocally confirmed by single-crystal X-ray structure analysis (Figure 2 ). 25 In general, the mechanism of the bidentate directing group picolinamide directing group-aided C–H activation and arylation of γ-C(sp 2 )–H bonds of benzylamine 3 , 6` b c d e or remote δ-C(sp 2 )–H bonds of phenethylamine types of molecules is well documented. 3 4 5a 6a , 9 10 11 12 13 14 15 In concurrence with literature reports, the intermolecular δ-C(sp 2 )–H functionalization reaction of phenylalaninols discussed in this paper is believed to undergo via the well-documented Pd II –Pd IV catalytic cycle.…”

“…3 6 For example, the functionalization of the ortho γ-C(sp 2 )–H bonds of aromatic amine substrates including benzylamine, phenylglycine, and phenylglycinol derivatives 1j have been well documented. 6` b c d e f g…”

Recent progress in catalytic acyloxylation of C(sp3)‐H bonds

“…Pd(II)‐catalyzed γ ‐C(sp 3 )‐H acetoxylation of ortho ‐toluidines of the type 21 , to form the corresponding 2‐aminobenzylacetates 22 (Scheme 5), was achieved using 5‐methylisoxazole‐3‐carboxamide (MICA) as a DG. [ 34 ] Pd(II)‐catalyzed acetoxylation was carried out under “standard” reaction conditions using Pd(OAc) 2 , acetoxylating agent PhI(OAc) 2 and a mixture of Ac 2 O/AcOH in toluene at high temperature (Scheme 5). Ortho ‐toluidine and several substituted toluidine derivatives were converted to γ ‐C(sp 3 )‐H acetoxylated products in 76–83 % yields.…”