Nicolle Schwarz

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

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.