Ruthenium-Catalyzed Anti-Markovnikov Hydroamination of Vinylarenes

Abstract

A ruthenium-catalyzed intermolecular, anti-Markovnikov hydroamination of vinylarenes with secondary aliphatic and benzylic amines is reported. The combination of Ru(cod)(2-methylallyl)2, 1,5-bis(diphenylphosphino)pentane, and triflic acid was the most effective catalyst of those tested. Control reactions conducted without ligand or acid did not form the amine. The reaction of morpholine, piperidine, 4-phenylpiperazine, 4-BOC-piperazine, 4-piperidone ethylene ketal, and tetrahydroisoquinoline with styrene in the presence of 5 mol % of this catalyst formed the corresponding beta-phenethylamine products in 64-96% yield, with 99% regioselectivity, and without enamine side products. Acyclic amines such as n-hexylmethylamine and N-benzylmethylamine reacted with styrene in 63 and 50% yields, respectively. Alkyl-, methoxy-, and trifluoromethyl-substituted styrenes reacted with morpholine in the presence of this catalyst or a related one containing 1,1'-bis(diisopropylphosphino)ferrocene as ligand to give the products in 51-91%. Further, the hydroamination of alpha-methyl styrene was observed for the first time with a homogeneous transition metal catalyst. Preliminary mechanistic studies showed that the reaction occurred by direct, irreversible, anti-Markovnikov hydroamination and that the mechanism of the ruthenium-catalyzed hydroamination is likely to be distinct from that of the recently reported rhodium-catalyzed reaction.

Transition‐Metal‐Catalyzed Hydroamination Reactions

“…Thus, by taking advantage of electron-withdrawing substituents in the para position of styrene substrates, Gunnoe and coworkers [256] were able to extend the intermolecular reactivity of these Cu(I) NHC complexes to the anti-Markovnikov hydroamination of select styrene derivatives with aniline as well as benzylamine (Scheme 15.58). While this contribution is a rare example of the anti-Markovnikov selective styrene hydroamination [105,132,133,145,245], the reactivity trends observed in this chemistry are consistent with the aza-Michael-type reactivity previously disclosed [248,249]. (47) have been prepared and rigorously characterized.…”

“…With styrene derivatives, the Markovnikov product is commonly obtained, as rationalized by the proposed mechanism. However, reliable methods for obtaining the anti-Markovnikov product have been developed using Ru-catalyzed hydroamination of vinyl arenes, in which η 6 -arene complexes are key catalytic intermediates (Scheme 15.17) [105,133]. This species promotes a nucleophilic attack at the β-carbon atom and catalytic turnover is achieved to realize selective anti-Markovnikov hydroamination with select amine nucleophiles [133].…”

Nucleophilic additions to polarized vinylarenes

“…In the absence of activating groups, hydroamination processes normally require transition metal catalysis. [15][16][17][18][19][20][21][22][23] The presumed mechanism for the reaction of 4a with 5a to give 1a is depicted in Figure 3. Deprotonation of 5a using DBU would generate DBU-H + and carbanion 14.…”

Titanium‐Catalyzed Intermolecular Hydroamination of Vinylarenes

“…[8,9] Significant research activity has focused on the use of late-transition-metal complexes for intermolecular hydroamination reactions of olefins, featuring iridium, [10][11][12] rhodium, [13][14][15][16][17][18] nickel, [19,20] palladium, [21][22][23][24] platinum, [25,26] and ruthenium. [27,28] The high cost of these complexes, their stabilizing ligands, or the additives constitute a limitation of these protocols. Recently, we reported a Group 4 metal catalyzed [29] intermolecular [30] hydroamination of norbornene.…”