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

Abstract

This paper reports the synthesis of enantiopure aryl alkyl ethers via the Pd(II)-catalyzed picolinamide-aided γ-C(sp 2 )À H alkoxylation of various enantiopure α-alkylbenzylamine derivatives using alcohols. Enantiopure α-methylbenzylamines and amino alcohol substrates such as 2amino-2-phenylethanol (phenylglycinol) and 3-amino-3-phenylpropanol were subjected to the γ-C(sp 2 )À H alkoxylation (etherification) with alcohols using PIDA. α-Alkylbenzylamines and phenylglycinols are valuable building blocks in organic synthesis and medicinal chemistry research areas. Accordingly, this work has enabled the assembling of various enantiopure ortho-alkoxylated α-methylbenzylamine and 2-amino-2-phenylethanol (phenylglycinol) and 3-amino-3-phenylpropanol derivatives containing aryl alkyl ether functionality. We have shown the utility of ortho-alkoxylated αmethylbenzylamine derivatives for assembling enantiopure α-methylbenzylamine-based sulfamoylcarbamates and carboxamides which are structurally related to the bio-active compounds known in the literature. This work demonstrates the substrate scope elaboration in CÀ H functionalization and etherification through the CÀ O bond-forming process and synthesis of aryl alkyl ether functionality containing enantiopure α-alkylbenzylamines.

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

“…Successively, we wished to establish the C(sp 2 )−H ( ortho ) arylation of 3‐amino‐3‐phenylpropanols ( γ ‐amino alcohols) which can be derived from β ‐phenylalanines. We recently reported a few ortho C−H oxygenation reactions using 3‐amino‐3‐phenylpropanol substrates 4 a – e ‐(RS) [7i] . We wished to obtain suitable reaction conditions for accomplishing the ortho C−H arylation of 3‐amino‐3‐phenylpropanol substrate 4 b ‐(RS) with aryl iodide 5 a in the presence of palladium catalysts, additives and solvents.…”

“…Next, the NaBH 4 ‐mediated reduction of the carboxylic acid group in 1 b ‐(RS) gave the corresponding 3‐amino‐3‐arylpropanols ( γ ‐amino alcohols). Then, 3‐amino‐3‐arylpropanols were used to assemble the corresponding 3‐amino‐3‐arylpropanol substrates 4 ‐(RS) possessing the PA or other DGs using standard conditions [7i] . Similarly, the enantiopure 3‐amino‐3‐arylpropanol substrates 4 a ‐(R) and 4 a ‐(S) linked with PA DG were assembled.…”

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

“…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…”

“…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.…”