Titanium‐Catalyzed Intermolecular Hydroaminoalkylation of Alkenes with Tertiary Amines

Abstract

The first cationic titanium catalyst system for the intermolecular hydroaminoalkylation of alkenes with various tertiary alkylamines is presented. Corresponding reactions which involve the addition of the a-CÀH bond of a tertiary amine across the CÀC double bond of an alkene take place at temperatures close to room temperature with excellent regioselectivity to deliver the branched products exclusively. Interestingly, for selected amines, a-C À H bond activation occurs not only at N-methyl but also at N-methylene groups.Tertiary amines are important structural motifs in natural products (e.g. alkaloids) and are indispensable for the development of agrochemicals or pharmaceuticals. [1] For example, more than 15 % of the 200 top selling small molecule drugs in 2018 contain a tertiary amine moiety. [1b] An attractive synthetic approach for the synthesis of various amines that has raised a lot of attention in recent years is the hydroaminoalkylation of alkenes which allows the 100 % atom economic addition of the a-C À H bond of simple amines across the C À C double bond of alkenes (Scheme 1). [2] Corresponding addition reactions can be achieved with late transition metal catalysts, [3] following a photo-catalytic approach, [4] or most efficiently with early transition metal catalysts. [5][6][7] In the latter case, neutral group 4 [5] and 5 [6] metal catalysts have extensively been used for a plethora of successful hydroaminoalkylation reactions of alkenes with primary or secondary amines (Scheme 1 a) but unfortunately, tertiary amines do not react successfully with alkenes in the presence of these catalysts. This lack of reactivity must be regarded as a severe restriction to the use of hydroaminoalkylation reactions, because it prohibits the use of simple tertiary amines as starting materials for the synthesis of more sophisticated tertiary amine products. Although a few late transition metal-catalyzed hydroaminoalkylation reactions with tertiary amines have been reported, [3,4] in these cases, the amine must contain an additional metal-binding directing

Stereoselective Synthesis of Tertiary Allylic Amines by Titanium‐Catalyzed Hydroaminoalkylation of Alkynes with Tertiary Amines

“…The latter result deserves particular attention because trimethylamine is a side product of the industrial production of methylamine and dimethylamine and according to the literature, [16] a lack of need for trimethylamine exists in the chemical industry because its conversion into useful products is difficult to achieve. With regard to substrate scope it must be mentioned that we did not observe any product formation with N , N ‐dimethylaniline, which is consistent with our previous observation that tertiary arylamines, do not undergo hydroaminoalkylation with alkenes in the presence of TiBn 4 and Ph 3 C[B(C 6 F 5 ) 4 ] [10f] …”

Photocatalytic Hydroaminoalkylation of Styrenes with Unprotected Primary Alkylamines

“…Perhaps the most attractive and atom-economical approach for the construction of α-alkylated amines is the net insertion of an alkene into an amine α-C–H bond, often termed a hydroamino­alkylation (HAA) reaction . For secondary and tertiary amines, the catalytic HAA of non-electrophilic alkenes has been dominated by early transition-metal-based catalysts. These reactions are typically sensitive to the substitution α to nitrogen, with the majority of reports focusing on N -methyl group functionalization, and linear selectivity being a particular challenge .…”

Titanium‐Catalyzed Intermolecular Hydroaminoalkylation of Alkenes with Tertiary Amines

“…After hydrochloride formation, we were able to unambiguously determine the structure of 5 b•HCl by single crystal X-ray diffraction (Figure 1). [16] Additional hydroaminoalkylation reactions performed with N-methylpyrrolidine (1 c) and various alkenes (2 a-d) then revealed that 1 c behaves similar but unfortunately, we were not able to seperate the two hydroaminoalkylation products which were formed in all theses reactions. However, corresponding product mixtures could be isolated in yields of 18-36 % and GC-analyses showed that again alkylation at the a-CH 2 -group of the heterocyclic ring is slightly favored.…”

“…Ellipsoids are drawn at the 50 % probability level. [16] Scheme 3. Multigram scale hydroaminoalkylation of 1-dodecene (2 d) with N-methylpiperidine (1 a).…”

“…Ellipsoid representation of the molecular structure of 5 b•HCl.Hydrogen atoms are omitted for clarity (exception H1, H1A and H8). Ellipsoids are drawn at the 50 % probability level [16].…”