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...

Kinetic studies on the intramolecular titanium‐catalyzed hydroaminoalkylation of alkenes (see scheme) are consistent with theoretical results and lead to the conclusion that the rate‐determining step of the catalytic cycle is the CH activation at the α position to the nitrogen atom. The reaction has a high activation energy and involves a moderately ordered transition state.

Owing to the great biological and industrial importance of nitrogen-containing molecules, much research has focused on the development of efficient methods for the synthesis of amines for a long time. Among various synthetic strategies, the hydroamination of alkenes and alkynes [1] and the hydroaminoalkylation of alkenes [2][3][4][5][6][7] must be regarded as particularly promising because both processes offer a direct and highly atom-efficient (100 %) conversion of simple starting materials into more complex molecules by CÀN or CÀC bond formation. During a hydroaminoalkylation reaction of an alkene, the a-CÀH bond of a primary or a secondary amine undergoes an addition across a CÀC double bond, which results in an alkylation of the amine in the a position to the nitrogen atom. Whilst simple tantalum catalysts [3,4] were initially used for this C À H activation process, corresponding enantioselective reactions could recently be achieved in the presence of chiral tantalum amidate complexes.[5] An additional class of suitable catalysts for hydroaminoalkylation reactions of alkenes are complexes of the Group 4 metals. [6,7] However, it must be noted that zirconium catalysts can only be used for intramolecular reactions of primary aminoalkenes, [7] whereas titanium catalysts, such as [Ti(NMe 2 ) 4 ] or [TiBn 4 ], catalyze intra-and intermolecular reactions, [6] and furthermore, titanium complexes show a higher catalytic activity than their zirconium counterparts. Upon inspection of intermolecular hydroaminoalkylation reactions of 1-alkenes reported in the literature, it becomes clear that the use of titanium catalysts usually results in the formation of two regioisomeric products (branched and linear; Scheme 1), whereas the branched regioisomer is formed exclusively in the presence of tantalum catalysts. Another interesting point is that efficient intermolecular hydroaminoalkylation reactions of styrenes have not been reported to date.[8] A possible explanation for this fact could be that hydroaminoalkylation reactions are usually performed under harsh reaction conditions (temperatures of 130-165 8C) [9] under which styrenes tend to undergo polymerization reactions.Based on the simple assumption that the regioselectivity of titanium-catalyzed intermolecular hydroaminoalkylation reactions and the results with styrenes may be improved by performing the reactions under milder conditions, we reinvestigated the catalytic performance of [Ti(NMe 2 ) 4 ] and [Ind 2 TiMe 2 ] (Ind = h 5 -indenyl), because with these two catalysts, the initially observed titanium-catalyzed hydroaminoalkylation reactions took place as side reactions during attempted intramolecular hydroaminations at a temperature of only 105 8C.[10]Initial intermolecular hydroaminoalkylation reactions of 1-octene (2) with N-methylaniline (1) performed in toluene [11] entries 1-4). Surprisingly, it was also found that with [Ind 2 TiMe 2 ] as the catalyst, the branched isomer 3 a is Scheme 1. Formation of regioisomers during intermolecular hydroaminomethylation re...

A detailed study of intra‐ and intermolecular hydroaminoalkylation reactions by activation of CH bonds adjacent to nitrogen atoms performed with a number of different titanium‐based catalysts and the identification of tetrabenzyltitanium ([TiBn4], Bn=benzyl) as a preferred catalyst for practical synthetic hydroaminoalkylation procedures is described. In the presence of 5 mol % of this catalyst, geminally disubstituted and unsub‐ stituted primary 1‐amino‐6‐heptenes undergo selective cyclizations to 1‐amino‐2‐methylcyclohexanes. In comparison to [Ti(NMe2)4], improved yields are obtained with [TiBn4] for most of the substrates. Only in the case of the strongly Thorpe–Ingold‐activated 1‐amino‐2,2‐diphenyl‐6‐heptene is a better yield obtained with [Ti(NMe2)4], especially when the reaction is performed at 145 °C. Whereas secondary N‐aryl aminoalkenes undergo intramolecular hydroaminoalkylation with poor efficiency, the corresponding intermolecular reactions of N‐aryl amines with alkenes can be achieved in the presence of 10 mol % of [Ti(NMe2)4] or [TiBn4]. With two exceptions, [TiBn4] again turned out to be catalytically more active than [Ti(NMe2)4]. A number of reactions which can not be achieved at all with [Ti(NMe2)4] take place in the presence of [TiBn4], including the first successful transition metal‐catalyzed hydroaminoalkylation of styrene by a CH activation process.

Hydroaminierungen von Alkinen und Alkenen [1] haben in den letzten Jahren erhebliche Aufmerksamkeit erhalten, da beide Verfahren einen atomökonomischen, einstufigen Zugang zu stickstoffhaltigen Molekülen eröffnen. Neben anderen Metallkatalysatoren [1] kamen für die genannten Reaktionen auch unterschiedlichste Ti-Katalysatoren zum Einsatz.[ [4d] Die hierfür erforderliche katalytische C-H-Aktivierung [5] am sp 3 -Zentrum in der aPosition zur primären Aminogruppe (die zuvor nie für Tikatalysierte Hydroaminierungen beschrieben wurde [6] ) ist, falls eine selektive Reaktionsführung gelingt, eine äußerst interessante chemische Transformation, denn sie würde eine direkte, 100 % atomökonomische Umwandlung einfacher Amine in komplexere Produkte unter C-C-Bindungsbildung ermöglichen.Ein Beispiel für eine ähnliche C-H-Aktivierung [5] an sp 3 -Zentren in der a-Position zum N-Atom [7,8] Um die Hydroaminierung zu unterdrücken, die prinzipiell mit der angestrebten C-H-Aktivierung konkurriert, bot sich die Verwendung eines um eine CH 2 -Gruppe verlängerten Substrates -eines 1-Amino-6-heptenderivats -an, da die entsprechende Hydroaminierung dann unter Bildung eines ungünstigen Siebenrings erfolgen müsste, während die über eine C-H-Aktivierung verlaufende Reaktion zum günstigen Sechsring führen würde. Erste Versuche mit 1-Amino-2,2-dimethyl-6-hepten (1, Schema 2) unter Verwendung von 5 Mol-% [Ti(NMe 2 ) 4 ] oder [Ind 2 TiMe 2 ] zeigten aber, dass die Bildung des angestrebten Cyclohexylamins 2 bei 105 8C langsam ist (< 10 % Umsatz (GC) nach 24 h). Erst eine Erhöhung der Reaktionstemperatur (160 8C) und eine Verlän-gerung der Reaktionszeit (72 h) ermöglichten in Gegenwart von [Ti(NMe 2 ) 4 ] die Isolierung des gewünschten C-H-Aktivierungsprodukts nach Überführung in das Tosylamid 3 in 46 % Ausbeute. Bemerkenswert ist, dass bei keiner der Reaktionen die Bildung des Hydroaminierungsproduktes, eines Azepans, beobachtet wurde. Entsprechend ist anzunehmen, dass 1-Amino-6-heptenderivate unter Verwendung von TiKatalysatoren offensichtlich bei hoher Temperatur selektiv zu Cyclohexylaminen umgesetzt werden können, ohne dass vorher eine Blockierung der primären Aminogruppe erforderlich ist.Da sekundäre Amine normalerweise keine Ti-katalysierten Hydroaminierungen eingehen, [3, 4a] ist die Umwandlung der primären in eine sekundäre Aminogruppe eine weitere Möglichkeit, die mit der angestrebten C-H-Aktivierung Schema 1. Bildung eines Cyclopentylamin-Nebenproduktes durch C-HAktivierung bei der Ti-katalysierten Hydroaminierung von Alkenen.[a] Zwei Diastereomere, cis/trans = 4:1. Ts = Toluol-4-sulfonyl.Schema 2. Selektive Bildung eines Cyclohexylaminprodukts aus einem 1-Amino-6-hepten.[a] Zwei Diastereomere, cis/trans = 2:5.