Titanium‐Catalyzed Hydroaminoalkylation of Alkenes by CH Bond Activation at sp³ Centers in the α‐Position to a Nitrogen Atom

Abstract

Hydroaminations of alkynes and alkenes [1] have attracted much attention during the past few years. Both transformations allow the synthesis of nitrogen-containing molecules in a single step with 100 % atom efficiency. Besides other metal catalysts, [1] titanium complexes have been used extensively for these reactions. [2][3][4] Recently, we recognized during a study of the Ti-catalyzed intramolecular hydroamination of alkenes that the cyclization of 1-amino-5-hexenes to piperidines (Scheme 1) performed with the catalysts [Ti(NMe 2 ) 4 ] or [Ind 2 TiMe 2 ] (Ind = indenyl) takes place along with the formation of aminocyclopentane side products.[4d] Interestingly, a corresponding catalytic C À H bond activation [5] at the sp 3 center in the a-position to a primary amino group has never been observed before during a Ti-catalyzed hydroamination.[6] However, this reaction would represent a very useful chemical transformation if it can be achieved selectively, because it offers a direct and highly atom-efficient conversion of simple amines to more complex molecules through C À C bond formation.A related example of C À H bond activation [5] at sp 3 centers in the a-position to nitrogen atoms [7, 8] is the [Ta(NMe 2 ) 5 ]-catalyzed intermolecular hydroaminoalkylation of alkenes described by Hartwig and Herzon.[9] Although only secondary N-arylated alkyl amines have been used for this reaction and [Zr(NMe 2 ) 4 ] was found to be catalytically inactive, the analogy to the formation of aminocyclopentane side products during Ti-catalyzed hydroaminations is obvious. For this reason, we became interested in whether Ti complexes such as [Ti(NMe 2 ) 4 ] and [Ind 2 TiMe 2 ] can generally be used as catalysts for selective hydroaminoalkylations of alkenes. To our knowledge and with the exception of the mentioned side reaction, [4d] corresponding Ti-catalyzed reactions have never been reported. [10] One possibility to suppress the intramolecular hydroamination that competes with the desired CÀH activation process is to use a 1-amino-6-heptene as the substrate. In this case, the hydroamination would lead to an unfavorable sevenmembered ring, while the C À H bond activation reaction would give a favored six-membered ring. Correspondingly, it can be expected that the desired aminocyclohexane will be formed selectively. Initial studies carried out with 1-amino-2,2-dimethyl-6-heptene (1, Scheme 2) and 5 mol % [Ti(NMe 2 ) 4 ] or [Ind 2 TiMe 2 ] revealed that the formation of the desired aminocyclohexane 2 is slow at 105 8C (less than 10 % conversion in 24 h, as determined by GC). However, when [Ti(NMe 2 ) 4 ] was used as the catalyst, an increase of the reaction temperature (160 8C) and a longer reaction time (72 h) resulted in the formation of the CÀH activation product 2, which could be isolated after conversion to the corresponding p-toluenesulfonamide derivative 3 (46 % yield). Particularly interesting is the fact that the formation of the hydroamination product, an azepane, has not been observed during the entire study performed w...

Transition‐Metal‐Catalyzed Hydroamination Reactions

“…However, they do help to inform continued catalyst development efforts, and general trends in the data included here show that steric congestion about the metal center can dramatically reduce reactivity. Another limitation of the cyclopentadienyl-derived catalysts is their illustrated propensity for forming unwanted side products (Scheme 15.7) that result from unexpected C-C bond formation in an intramolecular direct α-alkylation reaction, otherwise known as the hydroaminoalkylation reaction [50]. The formation of this side product is problematic when targeting the heterocyclic products; however, such reactivity is highly intriguing for the efficient preparation of amine-substituted carbocycles [51].…”

Catalytic synthesis of amines and N-containing heterocycles: Amidate complexes for selective C–N and C–C bond-forming reactions

“…Supplementary Information is available online (doi:10.1351/PAC-CON-09- [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27].…”

“…A similar mode of reactivity has been previously reported for Ti(NMe 2 ) 4 as a catalyst precursor [26] and is observed for high-oxidation-state group 5 based catalysts as well. Notably, a closely related strategy was recently used to catalytically α-alkylate secondary alkyl amines using Ti-based catalysts or simple homoleptic amido complexes and mixed amido chloro complexes of Ta [27][28][29][30]. For all of these transformations, the formation of metallaaziridines as key intermediates prior to the C-C bondforming step has been suggested.…”

“…Intermolecular hydroaminoalkylation using group 4 and 5 amido complexes (top) with a general mech anism for this C-C bond-forming reaction (bottom)[27,29,30].…”

Practical Alkoxythiocarbonyl Auxiliaries for Iridium(I)‐Catalyzed C−H Alkylation of Azacycles

“…Direct C–H arylation catalyzed by various transition metal have also been developed [7,8] . In the realm of direct C–H alkylation and related transformations, examples include transition metal-catalyzed C–H activation in the absence (Ta [9] , Ti [10] , Ru [11] catalysts) or presence of directing groups on nitrogen (Ru [12] , Ir [13] and Rh [14] catalysts) had been reported. These strategies generate versatile metal hydride species that can react with either alkenes or a variety of coupling partners such as alkynes and bis(pinacolato)diboron to deliver alkylated, alkenylated and borylated products.…”