Imines are of significant importance as intermediates for the synthesis of various amines and carbonyl compounds. In general, the synthesis of imines includes amination of a suitable aldehyde or ketone. A more atom-efficient route is the direct hydroamination of alkynes. [1] This method has the additional advantage that no water is produced as a by-product. Hence, various domino reactions (e.g. direct nucleophilic addition of organometallic reagents) are possible, which do not work in the presence of water.The homogeneously catalyzed intermolecular hydroamination of alkynes is known to proceed in the presence of Hg and Tl salts, [2] alkali metals (Cs), [3] Ti, [4] Zr, [5] Nd, [6] U, and Th [7] complexes. In addition, complexes of late-transition metals (such as Ru, Pd, [8] and Rh [9] ) have been used as catalysts for this transformation. Clearly, catalysts based on cheap and easily available titanium and zirconium complexes offer significant advantages compared to those based on toxic metals (Hg, Tl) or more expensive (U, Th, Ru, Pd, and Rh) complexes.Recently, important progress in the intermolecular hydroamination of alkynes with titanium complexes was made by Johnson and Bergman [10] and by Doye and co-workers. [4] While the former group developed the modified titanium complex [Cp(ArNH)(py)TiNAr] (Cp cyclopentadienyl, py pyridyl) and used it for the reaction of 2,6-dimethylaniline and diphenylacetylene, the latter group described an efficient and general method for the hydroamination of various internal alkynes using dimethyltitanocene as a catalyst. Bytschkov and Doye showed that the turnover frequency of this catalyst can be enhanced by using microwaves. [4c] Kinetic measurements by Bergman [10] and Doye [11] also established a general mechanism of the dimethyltitanocenecatalyzed intermolecular hydroamination of alkynes. Surprisingly little attention was paid to the hydroamination of terminal alkynes using titanium catalysts, [12] although the regioselective, sequential amination and hydroxylation of compounds that are unsaturated at the terminal position is one of the most challenging goals for industrial catalysis. Herein we report the first example of a titanocene-catalyzed anti-Markovnikov hydroamination of terminal aliphatic alkynes.Some time ago we started a program on catalytic amination reactions of olefins and alkynes. [13,9] Inspired by the work of Doye and Bergman, we also recently looked for easily available and stable titanocene complexes. Here, titanocene alkyne complexes of the type [Cp 2 Ti(h 2 -Me 3 SiCCR)] (Rosenthal×s catalyst) [14] appeared to be suited as amination catalysts. [15] These complexes ([Cp 2 Ti(h 2 -Me 3 SiCCSiMe 3 )] 1 [14a] and [Cp 2 Ti(h 2 -Me 3 SiCCPh] 2 [14b] ) are easily synthesized by reaction of titanocene dichloride with the corresponding silylated alkyne.Compared to previously used titanocene precatalysts, the titanacyclopropene complexes 1 and 2 are safe and stable under argon at room temperature for many months in German version. Indeed, hydroamination of...
A general study of the regioselective hydroamination of terminal alkynes in the presence of [(eta5-Cp)2Ti(eta2-Me3SiC2SiMe3)] (1), [(eta5-CpEt)2Ti(eta2-Me3SiC2SiMe3)] (CpEt=ethylcyclopentadienyl) (2), and [(eta5-Cp*)2Ti(eta2-Me3SiC2SiMe3)] (Cp*=pentamethylcyclopentadienyl) (3) is presented. While aliphatic amines give mainly the anti-Markovnikov products, anilines and aryl hydrazines yield the Markovnikov isomer as main products. Interestingly, using aliphatic amines such as n-butylamine and benzylamine the different catalysts lead to a significant change in the observed regioselectivity. Here, for the first time a highly selective switch from the Markovnikov to the anti-Markovnikov product is observed simply by changing the catalyst. Detailed theoretical calculations for the reaction of propyne with different substituted anilines and tert-butylamine in the presence of [(eta5-C5H5)Ti(=NR)(NHR)] (R=4-C6H4X; X=H, F, Cl, CH3, 2,6-dimethylphenyl) reveal that the experimentally observed regioselectivity is determined by the relative stability of the corresponding pi-complexes 10. While electrostatic stabilization favors the Markovnikov performance for aniline, the steric repulsive destabilization disfavors the Markovnikov performance for tert-butylamine.
A practical route for the synthesis of new biologically active 5-HT(2 A) receptor antagonists has been developed. In only three catalytic steps, this class of central nervous system (CNS) active compounds can be synthesized efficiently with high diversity. As the initial step, an anti-Markovnikov addition of amines to styrenes provides an easy route to N-(arylalkyl)piperazines, which constitute the core structure of the active molecules. Here, base-catalyzed hydroamination reactions of styrenes with benzylated piperazine proceeded in high yield even at room temperature. After catalytic debenzylation, the free amines were successfully carbonylated with different aromatic and heteroaromatic halides and carbon monoxide to yield the desired compounds in good to excellent yields. The two key reactions, base-catalyzed hydroamination of styrenes and palladium-catalyzed aminocarbonylation of haloarenes/heterocycles, showed tolerance towards various functional groups, thereby demonstrating the potential to synthesize a wide variety of new derivatives of this promising class of pharmaceuticals.
Professor Lutz F. Tietze zum 60. Geburtstag gewidmet Als Intermediate bei der Synthese von Aminen und Carbonylverbindungen sind Imine von gro˚er Bedeutung. Sie sind im Allgemeinen durch Aminierung eines Aldehyds oder Ketons leicht zug‰nglich. Eine atomeffizientere Route ist die direkte Hydroaminierung von Alkinen, [1] die ohne Bildung von Wasser als Nebenprodukt verl‰uft und daher Folgereaktionen wie die direkte nucleophile Addition von Organometallverbindungen ermˆglicht, die in Gegenwart von Wasser nicht stattfinden. Es ist bekannt, dass die homogen katalysierte intermolekulare Hydroaminierung von Alkinen in Gegenwart von Hgund Tl-Salzen, [2] Alkalimetallen (Cs), [3] Ti-, [4] Zr-, [5] Nd-, [6] Uund Th-Komplexen [7] verl‰uft. Auch Komplexe sp‰ter ‹bergangsmetalle (z. B. Ru, Pd [8] und Rh [9] ) wurden als Katalysatoren f¸r diese Reaktionen eingesetzt. Preiswerte und leicht zug‰ngliche Titan-und Zirconium-Katalysatoren sind nat¸rlich solchen mit toxischen (Hg, Tl) oder teuren Metallen (U, Th, Ru, Pd und Rh) vorzuziehen. Johnson und Bergman [10] sowie Doye et al. [4] erzielten k¸rzlich wichtige Fortschritte auf dem Gebiet der intermolekularen Hydroaminierung von Alkinen mit Titan-Komplexen. Die Arbeitsgruppe um Bergman synthetisierte den modifizierten Titanocenkomplex [Cp(ArNH)(py)TiNAr] (Cp Cyclopentadienyl; py Pyridyl) und testete ihn in der Reaktion von Diphenylacetylen und 2,6-Dimethylanilin. Doye et al. berichteten¸ber ein effizientes und breit anwendbares Verfahren zur katalytischen Hydroaminierung von disubstituierten Alkinen unter Verwendung von Dimethyltitanocen als Katalysator. Bytschkov und Doye [4c] konnten zeigen, dass die Turnover-Frequenzen durch Mikrowellenbestrahlung drastisch erhˆht werden. Anhand kinetischer Untersuchungen [10, 11] wurde der Mechanismus der Dimethyltitanocen-katalysierten intermolekularen Hydroaminierung von Alkinen weitgehend gekl‰rt. ‹berraschenderweise wurde der Hydroaminierung terminaler Alkine mit Titan-Katalysatoren [12] wenig Aufmerksamkeit geschenkt, obwohl die regioselektive Aminierung und Hydroxylierung terminaler unges‰ttigter Verbindungen unter Bildung der linearen Produkte eine der grˆ˚ten Herausforderungen f¸r die industrielle Katalyse ist. Wir berichten hier¸ber ein erstes Beispiel der Titanocen-katalysierten Anti-Markownikow-Hydroaminierung terminaler Alkine.Wir besch‰ftigen uns bereits seit einigen Jahren mit der katalytischen Aminierung von Olefinen und Alkinen [13,9] und dehnten unsere Forschungen ± inspiriert durch die Arbeiten von Doye et al. und Bergman et al. ± nun auf die Hydroaminierung aliphatischer Alkine mit prim‰ren aliphatischen und aromatischen Aminen in Gegenwart von Titanacyclopropen-Komplexen des Typs [Cp 2 Ti(h 2 -Me 3 SiCCR)] (Rosenthal-Katalysatoren) aus. [14, 15] Die hier verwendeten Komplexe [Cp 2 Ti(h 2 -Me 3 SiCCSiMe 3 )] 1 [14a] und [Cp 2 Ti(h 2 -Me 3 -SiCCPh)] 2 [14b] sind durch Umsetzung von Titanocendichlorid mit silylierten Alkinen leicht zug‰nglich.Anders als die fr¸her verwendeten Titanocen-Pr‰katalysatoren lassen sich die Titanac...
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