Annegret Tillack

Base-Catalyzed Hydroamination of Olefins: An Environmentally Friendly Route to Amines

The base-catalyzed hydroamination of olefins offers a simple and elegant access to various primary, secondary, and tertiary amines. Particular focus is placed on developments in the area of hydroamination of non-activated olefins. Advantages and disadvantages of the methodology compared to other synthetic methods are presented. Special attention is paid to potential industrial applications of this chemistry.

Catalytic Amination of Aldehydes to Amides

Aldehydes react in a disproportionation reaction in the presence of rhodium catalysts to yield amines and amides. By adding N-methylmorpholine N-oxide as an oxidant in the presence of catalytic amounts of rhodium, the oxidative amination of aldehydes proceeds selectively to give the corresponding amide. Both aliphatic and aromatic aldehydes react with secondary amines to yield carboxylic acid amides in good to excellent yields.

Zinc-promoted hydrohydrazination of terminal alkynes: an efficient domino synthesis of indoles.

There is continuing interest in the development of improved methods for the synthesis of indoles owing to their importance as one of the most represented building block in natural bioactive products and marketed drugs. Thus, indole and its derivatives have been termed “privileged pharmacological structures” as they bind to many biological receptors with high affinity. In recent years, domino sequences in particular have provided efficient complementary access to various indoles. Such sequences start in general from easily available substrates. A reactive intermediate is generated with the aid of a catalyst, which is subsequently transformed to the desired indole. For example, the domino hydroformylation–Fischer indole sequence has evolved into a direct method for the onepot construction of complex indoles from olefins. More recently, Ackermann and Born reported the use of a combination of TiCl4 and tBuNH2 as catalyst for the domino hydroamination–Fischer indole cyclization. In 1991, Bergman et al. reported the first zirconium-mediated synthesis of indoles by trapping a hydrazidozirconocene complex with alkynes and subsequent addition of hydrochloric acid. Then, Odom and co-workers described the first titanium-catalyzed intermolecular hydroamination of arylhydrazines with alkynes. The arylhydrazones obtained have been used further in the Fischer indole reaction to provide N-alkyl and N-aryl indoles in high yield. Based on this elegant approach, we have developed the titanium-catalyzed synthesis of functionalized tryptamines and tryptamine homologues, and tryptophol and tryptophol derivatives, starting from commercially available arylhydrazines and alkynes. A problem which prevents widespread use of this reaction is the sensitivity of the titanium complexes towards functional groups, and the necessity for hydrazine protection and indole deprotection steps. Our continuing interest in indole syntheses led us to look for alternative catalysts for the intermolecular hydrohydrazination. Herein we report the intermolecular zinc-mediated and -catalyzed hydroamination reactions of alkynes which provide a general synthesis of indoles. Our initial investigations involved studying the effect of different metal complexes on themodel reaction ofN-methylN-phenylhydrazine 1a with 1-octyne 2a (Table 1). The

Selective Ruthenium‐Catalyzed N‐Alkylation of Indoles by Using Alcohols

Indoles constitute important heterocyclic systems in nature. Based on the broad structural diversity and due to their biological activity, indoles have become an important component in several current pharmaceutical drugs. Hence, the development of improved synthetic methodologies for the generation of the indole core, as well as functionalization reactions on the aromatic ring system continue to be of significant interest to organic chemists. Among the numerous known bioactive indoles, various N-alkylated derivatives are known. The classical approach for the introduction of these alkyl chains involves treatment of the indole with base and an alkyl halide. A drawback of these reactions is the quantitative formation of waste salts. Clearly, this disadvantage can be overcome by using easily available alcohols as a more benign alkyl source. However, so far, the N-alkylation of indoles with alcohols has only been investigated in the presence of Raney nickel. More recently, Grigg and co-workers demonstrated that simple alcohols can be used for selective C-3-alkylation of indoles. This reaction is based on the so-called “borrowing hydrogen” methodology. Thereby, an alcohol or amine is initially dehydrogenated, then undergoes a functionalization reaction, and finally is rehydrogenated. Applications of this elegant methodology have been developed by the groups of Yus, Fujita, Grigg, Kempe, and us. Based on our ongoing interest in the synthesis of novel indoles and the activation of alcohols, we became interested in the selective N-alkylation of this important class of natural products. At the start of our investigations we studied the reaction of indole with hexanol as a model system. In general, this alkylation might result in N-, C-, and dialACHTUNGTRENNUNGkylated products (Scheme 1).

Ruthenium‐catalyzed Selective Monoamination of Vicinal Diols

The monoamination of vicinal diols in the presence of in situ generated ruthenium catalysts has been investigated. Among the various phosphines tested in combination with [Ru(3)(CO)(12)], N-phenyl-2-(dicyclohexyl-phosphanyl)pyrrole showed the best performance. After optimization of the reaction conditions this system was applied to different secondary amines and anilines as well as a number of vicinal diols. With the exception of ethylene glycol, monoamination of the vicinal diols occurred selectively and the corresponding amino alcohols were obtained in good yields, producing water as the only side product.

Zinc-catalyzed synthesis of pyrazolines and pyrazoles via hydrohydrazination.

A novel regioselective synthesis of aryl-substituted pyrazolines and pyrazoles has been developed. Substituted phenylhydrazines react with 3-butynol in the presence of a catalytic amount of zinc triflate to give pyrazoline derivatives. The resulting products are easily oxidized in a one-pot procedure to the corresponding pyrazoles.

General Zinc‐Catalyzed Intermolecular Hydroamination of Terminal Alkynes

Catalytic hydroaminations are one of the most sustainable C-N bond-forming processes as a result of 100% atom economy and the availability of substrates. Here, it is shown that the intermolecular hydroamination of terminal alkynes with anilines proceeds smoothly in the presence of catalytic amounts of zinc triflate, an easily available and inexpensive zinc salt. Amination and subsequent reduction with NaBH3CN gives a variety of secondary and tertiary amines in up to 99% yield and with over 99% Markovnikov regioselectivity. Moreover, difficult functional groups such as nitro and cyano substituents are tolerated by the homogeneous catalyst.

Intramolekulare Cyclisierung von terminal disubstituierten α, ω-Diinen an Titanocen “Cp2Ti” mit einer nachfolgenden, ungewöhnlichen Cp-ringöffnung und neuen intramolekularen CC-Knüpfung

Abstract The reaction of Cp 2 Ti(Me 3 SiC 2 SiMe 3 ) ( 1 ) with terminal disubstituted α,ω-diynes RC≡C(CH 2 ) n C≡CR affords, after substitution of Me 3 SiC 2 SiMe 3 , bicyclic titanacyclopentadienes via intramolecular cyclization. The stability of the obtained products 2, 3 and 5 is determined by the spacer length ( n = 2, 4, 5, 6). The four-membered ring derivatives ( n = 2) 2a and 2b were obtained in good yield. In the case of n = 4 the bicyclic six-membered ring 3 was formed at first, which rearranges to a stable tricyclic η 4 : η 3 -dihydroindenyl-Ti complex 4 by Cp cleavage and intramolecular CC coupling. Complex 4 was characterized by X-ray structure analysis and NMR spectroscopy. An increase of spacer length ( n > 4) provides indefinable secondary and decomposition products.

Regioselektive reaktionen der fremdligandfreien titanocen-alkin-komplexe Cp2Ti(RC2SiMe3) (R = Me3Si,Ph, tBu, nBu)☆

Abstract Depending on different substituents in the reaction of Cp 2 TiCl 2 with magnesium and the alkynylsilanes RC≡CSiMe 3 (R = SiMe 3 , Ph, t Bu, n Bu, n Pr, Me) in tetrahydrofuran, titanacyclopropenes (R = SiMe 3 , Ph, t Bu 1 , n Bu 2 ), symmetrical substituted titanacyclopentadienes (R = Me 5 ) or in a competition reaction both types of complexes (R = n Pr 3 and 4 ) were obtained. The compound Cp 2 Ti( t BuC 2 SiMe 3 ) 1 is the first example of a titanocene complex with an alkyl substituted alkyne without further ligands and was characterized by X-ray crystal structure analysis. The structural and spectroscopical data of 1 were compared with those of other well known complexes of that type, e.g. Cp 2 Ti(Me 3 SiC 2 SiMe 3 ) and Cp 2 Ti(PhC 2 SiMe 3 ) to investigate the influence of different substituents ( t Bu, SiMe 3 , Ph) upon alkyne complexation. The chemo- and regio-selectivities of the obtained alkyne complexes was studied in reactions with alkynes, alcohols, carbon dioxide and acetone. The reaction course depends mostly on steric restrictions, being in the first step kinetically favored at the Si-substituted C-atom of the alkyne and giving β-SiMe 3 -substituted products, which rearrange in some cases into the thermodynamically more stable α-SiMe 3 -substituted products.

A Base-Catalyzed Domino-Isomerization–Hydroamination Reaction—A New Synthetic Route to Amphetamines

Abstract An efficient synthesis of pharmaceutically interesting amphetamines by a base-catalyzed domino-isomerization–hydroamination reaction is presented. Starting from allylbenzene and various primary or secondary amines, the basic structural pattern of amphetamines is synthesized directly in yields of up to 91% in the presence of catalytic amounts of n -butyllithium.