Theoretical Studies on the Hydroaminoalkylation of Alkenes with Primary and Secondary Amines

Abstract

The α-alkylation of amines with alkenes catalyzed by early transition-metal complexes represents an efficient and atom economic method for the synthesis of functionalized amines from simple and easily available starting materials. While the successful use of secondary amines, such as dimethylamine, strongly underlines the enormous industrial potential of this reaction, the analogous intermolecular α-alkylation of primary amines, especially methylamine, remains an unsolved synthetic task to this day. Based on calculated thermodynamic data, these experimental findings can now be explained for the first time, whereby several competing reactions, which are explained in detail, are of crucial importance for the different behavior of primary and secondary amines.

Computational Investigation of Scandium-Based Catalysts for Olefin Hydroaminoalkylation and C–H Addition

“…Therefore, the development of effective approaches toward amine functionalization has attracted considerable interests in the past few decades . Of the possible approaches, the catalytic olefin hydroaminoalkylation by using amines is an atom-efficient method to synthesize alkylated amine derivatives. − Significant advances have been made in early-transition-metal-catalyzed hydroaminoalkylation. − These reactions are generally thought to initially go through the formation of metal amido intermediates via deprotonation of an N–H bond, which limits the amine substrates to primary and secondary amines . Although olefin hydroaminoalkylation by using tertiary amines can be accomplished through late-transition-metal catalysts, , the reactions are often limited to the amines having a directing group such as pyridyl .…”

Fast Titanium‐Catalyzed Hydroaminomethylation of Alkenes and the Formal Conversion of Methylamine

“…It is also noteworthy that we were unable to successfully convert an alkene containing a tertiary amine (Table , entry 9). We suspect the tertiary amine to partially deprotect 3 , free methylamine would then immediately disable the catalyst . This finding suggests that a successful conversion of a tertiary amine can only be expected when high steric bulk is present near the amino group.…”

“…We also discovered that this catalytic system is active enough to even convert silyl‐protected primary amines such as the TBDMS‐protected methylamine 3 (Scheme ) giving direct access to silyl‐protected primary amines by hydroaminomethylation. Although the conversion of primary aminoalkenes in an intramolecular hydroaminoalkylation has been achieved in the past, the conversion of primary amine substrates (and consequently the synthesis of primary amine products) in an intermolecular hydroaminoalkylation has unfortunately been almost impossible, most notably because of the formation of metal–imido species or bridging towards multinuclear metal complexes, which deactivates the catalyst . This limited scope poses a very severe restriction to the use of hydroaminoalkylation reactions, especially because it prohibits the use of the most important primary amine, methylamine.…”

Fast Titanium‐Catalyzed Hydroaminomethylation of Alkenes and the Formal Conversion of Methylamine

“…Although the conversion of primary aminoalkenes in an intramolecular hydroaminoalkylation has been achieved in the past, [3,8] thec onversion of primary amine substrates (and consequently the synthesis of primary amine products) in an intermolecular hydroaminoalkylation has unfortunately been almost impossible,m ost notably because of the formation of metal-imido species or bridging towards multinuclear metal complexes,which deactivates the catalyst. [14] This limited scope poses av ery severe restriction to the use of hydroaminoalkylation reactions,e specially because it prohibits the use of the most important primary amine,m ethylamine.D uring the writing of this manuscript, am ethod for the conversion of silyl-protected benzylamine was published, but was limited exclusively to the activated amine and an arrow scope of alkenes,w ith reaction times of 24-240 h. [15] By using the already described method with the in situ generated catalyst and TBDMS-protected methylamine 3 as the amine substrate (see Scheme 2), we were able to generate primary amine products in good yield after reaction times of 12 h. After completion of the catalysis,the free primary amine can be obtained by hydrolysis.The simplest method we found was to simply treat the diluted crude reaction mixture with wet solvent (CH 2 Cl 2 /MeOH/H 2 O = 75:25:1) overnight at room temperature.A lternatively,i fafaster workup is required, the deprotection can also be achieved by stirring the crude reaction mixture in boiling EtOH/H 2 O(4:1) for one minute.…”

“…We suspect the tertiary amine to partially deprotect 3,f ree methylamine would then immediately disable the catalyst. [14] This finding suggests that asuccessful conversion of atertiary amine can only be expected when high steric bulk is present near the amino group.O verall, the results show that the tolerance towards steric properties of the substrate varies largely,b ut as terically less demanding alkene is generally advantageous.M any alkenes and functional groups are tolerated very well, including dienes,e thers,p rotected alcohols,and silanes (Table 3, entries 3, 5-8, 12).…”