synthesis and catalytic functionalization of biologically active indoles

DOI: 10.1002/cssc.200700160
General Zinc-Catalyzed Intermolecular Hydroamination of
Terminal Alkynes
Karolin Alex, Annegret Tillack, Nicolle Schwarz, and Matthias Beller* [a]
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
Introduction
The addition of primary and secondary amines to C C unsaturated
bonds represents an attractive and green method for the
synthesis of nitrogen-containing organic compounds. As a
result of 100 % atom economy and the availability of substrates,
catalytic hydroaminations constitute probably the most
sustainable C N bond-forming processes. [1] While a general
and efficient hydroamination of aliphatic alkenes is not yet
possible and still a major challenge in modern catalysis research,
alkynes are more reactive in hydroamination reactions.
In general, terminal alkynes can provide two regioisomeric
imines, the Markovnikov and the anti-Markovnikov product
(Scheme 1). Typically, the Markovnikov regioisomer is thermodynamically
favored.
Scheme 1. Hydroamination of terminal alkynes.
As a result of the continuing interest in alkyne hydroamination,
several catalysts have been developed over the last
decade for the intra- and intermolecular hydroamination of
non-activated alkynes. Pioneering work in this area was reported
by Barluenga et al., who employed mercury and thallium
salts for the hydroamination of alkynes with anilines, and special
work was done by Reppe using acetylene in the presence
of zinc and cadmium salts. [2] Later on, the intermolecular hydroamination
of alkynes was carried out with lanthanides (Sm,
Lu, Nd) and actinoids (Ur, Th), early transition metals (Zr, Ti, V,
Ta), Ru, Rh, Pd, Pt, Ag, and Au. [3] Despite the methodological
progress, the application of most of these catalyst systems is
narrowed by their air and/or moisture sensitivity and/or their
limited ability to tolerate different functional groups.
and subsequent reduction with NaBH 3CN 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.
In addition to the well-established organometallic complexes
used for hydroaminations, also heterogeneous catalysts based
on transition-metal-exchanged montmorillonite K-10 (Cu 2 + ) [4]
and solid catalysts based on supported ionic liquids (Zn, Cu,
Pd, Rh) [5] were reported for the reaction of aniline derivatives
with phenylacetylene. Among the different metal catalysts
known for hydroaminations, extensive investigations have
been reported on Ti-based catalysts because of the price of
the metal and their low toxicity. [6] Notably, the Markovnikov or
the anti-Markovnikov functionalization of alkynes can be controlled
by applying a suitable ligand in the Ti complex. [7]
Besides the hydroamination with simple amines and alkynes,
similar reactions with other nitrogen nucleophiles such as hydrazines
are known. In this respect, the hydrohydrazination
with subsequent Fischer indole synthesis is especially noteworthy.
[8] Recently, we reported for the first time an intermolecular
zinc-mediated and -catalyzed hydrohydrazination reaction of
alkynes which allows for a general synthesis of indoles
(Scheme 2). [9] On the basis of this investigation, we became interested
in the use of zinc catalysts for the hydroamination of
alkynes with amines. To the best of our knowledge, there is no
homogeneous zinc catalyst known for any intermolecular hydroamination
of alkynes with amines. Müller and co-workers
demonstrated that the reaction of phenylacetylene with 4-isopropylaniline
in the presence of ZnACHTUNGTRENUNG(OTf) 2 proceeded only with
3 % conversion. [5] However, the thermodynamically more favorable
intramolecular hydroamination of terminal alkynes is
known to be catalyzed by homogeneous zinc catalysts, which
has been nicely demonstrated by Müller and co-workers as
well as by Blechert, Roesky et al. [10]
[a] K. Alex, Dr. A. Tillack, N. Schwarz, Prof. Dr. M. Beller
Leibniz-Institut für Katalyse e.V. an der Universität Rostock
Albert-Einstein-Strasse 29a
18059 Rostock (Germany)
Fax: (+ 49)381 1281 51113
E-mail: matthias.beller@catalysis.de
ChemSusChem 2008, 1, 333 – 338 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemsuschem.org 333