Iron-Catalyzed Anti-Markovnikov Hydroamination and Hydroamidation of Allylic Alcohols

Abstract

Hydroamination allows for the direct access to synthetically important amines. Controlling the selectivity of the reaction with efficient, widely applicable, and economic catalysts remains challenging, however. This paper reports an iron-catalyzed formal anti-Markovnikov hydroamination and hydroamidation of allylic alcohols, which yields γ-amino and γ-amido alcohols, respectively. Homoallylic alcohol is also feasible. The catalytic system, consisting of a pincer Fe-PNP complex (1–4 mol %), a weak base, and a nonpolar solvent, features exclusive anti-Markovnikov selectivity, broad substrate scope (>70 examples), and good functional group tolerance. The reaction could be performed at gram scale and applied to the synthesis of drug molecules and heterocyclic compounds. When chiral substrates are used, the stereochemistry and enantiomeric excess are retained. Further application of the chemistry is seen in the functionalization of amino acids, natural products, and existing drugs. Mechanistic studies suggest that the reaction proceeds via two cooperating catalytic cycles, with the iron complex catalyzing a dehydrogenation/hydrogenation process while the amine substrate acts as an organocatalyst for the Michael addition step.

Anti‐Markovnikov Hydroamination of Racemic Allylic Alcohols to Access Chiral γ‐Amino Alcohols

“…We recently showed the feasibility of formal anti‐Markovnikov hydroamination of allylic alcohols with an achiral iron catalyst via hydrogen borrowing [12] . Our further work using a similar approach has revealed that the Guerbet reaction can be made enantioselective with a chiral Ru‐diamine‐diphosphine catalyst, in which an intermediary ketone is reduced to a chiral alcohol product [10q] .…”

“…Quintard [8] and Dydio [9] have elegantly demonstrated that primary allylic alcohols could react with carbon nucleophiles via hydrogen‐borrowing to afford γ‐chiral primary alcohols, [10] in which an achiral hydrogen‐borrowing catalyst is cascaded with a chiral C−C coupling catalyst (Figure 1 c). Oe [11] and more recently we [12] have shown that the hydrogen‐borrowing strategy could be employed for the formal anti‐Markovnikov hydroamination of allylic alcohols to give racemic γ‐amino alcohols. This finding could offer a new pathway for chiral γ‐amino alcohols, departing from the common asymmetric hydroamination strategy.…”

Control of Absolute Stereochemistry in Transition‐Metal‐Catalysed Hydrogen‐Borrowing Reactions

“…For the alkylation of alanineand serine (31 d and 31 e,respectively), as mall amount of racemization was observed, but in the majority of cases the productsw ere obtained with near perfecte nantiospecificity. [16] Cumpstey,M artín-Matute and co-workers have shown that alcohols and amides which are both derived from carbohydratesc an be coupled under hydrogen-borrowingc onditions to afford amino sugarss uch as 34 (Scheme 9). [17] Both the amine anda lcohol partners reactedw ithoute rosiono fs tereochemistry to afford the products with complete diastereoselectivity.…”

On the Use of Iron in Organic Chemistry

“…Hydroamination of alkenes is an atom-economic approach and the amines produced are some of the most common functionalities found in fine chemicals and pharmaceuticals. Hydroamination of terminal alkenes typically gives the Markovnikov product selectivity, but in 2019 the group of Wang reported the first iron-catalyzed anti-Markovnikov addition of allylic alcohols [21]. For this purpose, an iron-PNP pincer complex was used.…”