Oxa‐Michael Addition to α,β‐Unsaturated Nitriles: An Expedient Route to γ‐Amino Alcohols and Derivatives

Abstract

Water addition to α,β‐unsaturated nitriles would give facile access to the β‐hydroxy‐nitriles, which in turn can be hydrogenated to the γ‐amino alcohols. We have previously shown that alcohols readily add in 1,4‐fashion to these substrates using Milstein's Ru(PNN) pincer complex as catalyst. However, attempted water addition to α,β‐unsaturated nitriles gave the 3‐hydroxynitriles in mediocre yields. On the other hand, addition of benzyl alcohol proceeded in excellent yields for a variety of β‐substituted unsaturated nitriles. Subsequent treatment of the benzyl alcohol addition products with TMSCl/FeCl3 resulted in the formation of 3‐hydroxy‐alkylnitriles. The 3‐benzyloxy‐alkylnitriles obtained from oxa‐Michael addition also could be hydrogenated directly in the presence of acid to give the amino alcohols as their HCl salts in excellent yields. Hydrogenation under neutral conditions gave a mixture of the secondary and tertiary amines. Hydrogenation in the presence of base and Boc‐anhydride gave the orthogonally bis‐protected amino alcohols, in which the benzyl ether can subsequently be cleaved to yield Boc‐protected amino alcohols. Thus, a variety of molecular scaffolds with a 1,3‐relationship between O‐ and N‐functional group is accessible starting from oxa‐Michael addition of benzyl alcohol to α,β‐unsaturated nitriles.

Catalytic Conversion of Nitriles by Metal Pincer Complexes

“…In a later publication, the nitrile scope was further extended to more challenging structures containing β-substituents such as CF 3 , p-CF 3 C 6 H 4 and cyclopentyl. Here the products were obtained in moderate to good yields [88]. Unfortunately, phenols deactivated the catalyst by strongly binding to the ruthenium.…”

Accessing Medicinally Relevant O‐Benzofused Heterocycles through C−X Activation: Recent Trends

“…[22] Although, the first Oxa-Michael reaction was established in 1878, to prepare maleic acid, it was largely ignored due to its the reduced reactivity and selectivity. Currently, this strategy represents a reliable tool to produce versatile synthons such as β-amino alcohols [23] and β-hydroxycarbonyls [24] through CÀ O bond formation, which make them valuable candidates for the preparation of O-heterocycles, and particularly benzofused types. In this context, Reddy et al reported the regioselective synthesis of 3-arylsulfonylbenzofurans, naphthofurans and furanopyridine derivatives via palladium-catalyzed annulation of halophenols with β-iodovinyl sulfones (Scheme 5).…”

Catalyst H-ZSM 5 in Amines addition on Carbonyl Compounds α, β-unsaturated catalyzed by H-ZSM 5

“…The addition of a series of amines to α, β-unsaturated alkenes, [8] an interesting methodology for [9] for the e cient coupling of amines with a wide range of α, β-unsaturated carbonyl components [10], to obtain the excellent products show the role of a material like HMZ5 in reactions in organic chemistry [11].…”