ChemComm
Cite this: Chem. Commun., 2011, 47, 7815–7817
COMMUNICATION
Au-catalyzed synthesis of 2-alkylindoles from N-arylhydroxylamines and
terminal alkyneswz
Yanzhao Wang, Longwu Ye and Liming Zhang*
Received 17th April 2011, Accepted 9th May 2011
DOI: 10.1039/c1cc12212f
The first gold-catalyzed addition of N-arylhydroxylamines to
aliphatic terminal alkynes is developed to access O-alkenyl-N-
arylhydroxylamines, which undergo facile in situ sequential 3,3-
rearrangements and cyclodehydrations to afford 2-alkylindoles
with regiospecificity and under exceptionally mild reaction
conditions.
hydroxyamine have not been used as nucleophiles.10 In con-
tinuation of our research on gold catalysis, we anticipated that
gold complexes could be employed in Scheme 1 to promote the
formation of O-alkenyl-N-arylhydroxylamine 1 via activation
of alkynes toward nucleophilic attack. Herein, we disclose a
regiospecific synthesis of 2-alkylindoles via the annulation of
N-arylhydroxylamines and terminal alkynes under mild reaction
conditions.
The Fischer indole synthesis1 is perhaps the most versatile
method for the construction of indole rings2 and has been
applied extensively in the synthesis of various indole alkaloids3
since the original report by Fischer4 more than one hundred
years ago. This annulation between an arylhydrazine and
a ketone relies on a key 3,3-sigmatropic rearrangement of an
N-alkenyl-N0-arylhydrazine intermediate. While it has been
subjected to various modifications/improvements,5 there are
still notable deficiencies including the often difficulty in achieving
excellent regioselectivities with non-symmetric ketones and
demanding reaction conditions such as strong acidities and/
or elevated reaction temperatures.
We started by using N-phenylhydroxylamine and 1-dodecyne
(2 equiv) as substrates and Ph3PAuNTf2 as the catalyst.
To our delight, 2-n-decylindole 3a11 was indeed formed after
reacting at room temperature for 18 h (Table 1, entry 1), and
methyl ketone 4a was the major side product. Due to the
disproportionation of the hydroxylamine substrate, some aniline
and trace amount of diazene N-oxide 5a were observed.
We attributed the formation of ketone 4a partly to the
competitive N–H addition of the hydroxylamine to 2a
followed by subsequent hydrolysis (eqn (1)) and partly to
direct gold-catalyzed hydration. H2O consumed in these
processes should mostly come from the cyclodehydrative
indole formation. Screening different gold catalysts (entries
2–7) revealed that phosphite-based cationic gold(I) complex,
(ArO)3PAuNTf2 (Ar = 2,4-di-tert-butylphenyl), gave the best
result (entry 4). Somewhat to our surprise, DCE was a better
solvent than DCM, and the yield was up to 94% (entry 8).
Additional solvents (entries 10–14) were examined, and both
diethyl ether (entry 10) and toluene (entry 13) were excellent
choices as well. The reaction yield decreases as the amount of
the alkyne decreases (entries 15 and 16). With 1.8 equivalents
of 1-dodecyne (entry 15), the reaction yield was still very good,
and the isolated yield was 84%.
Similarly, 3,3-rearrangements of O-vinyl-N-arylhydroxyl-
amines or their derivatives6 can lead to indole synthesis upon
subsequent cyclodehydration. A notable example is the Bartoli
indole synthesis.7 While this rearrangement typically proceeds
at much lower temperatures than in the case of the Fischer
indole synthesis, there is a lack of general and straigthforward
methods6 for the generation of O-alkenyl-N-arylhydroxy-
amines. We envisioned that these intermediates could be
formed via metal-promoted additions of the HO groups of
N-arylhydroxylamines onto C–C triple bonds (Scheme 1). By
using alkynes as substrates, this indole synthesis may provide
solutions to some of the deficiencies in the Fischer indole
synthesis. Surprisingly, this strategy has not been realized
although related ones using propiolates and hydroxamic acids
in the presence of bases have been reported.8
Efficient additions of various nucleophiles (NuH) to C–C
triple bonds have been realized in gold catalysis;9 however,
Department of Chemistry and Biochemistry, University of California,
Santa Barbara, CA 93106, USA. E-mail: zhang@chem.ucsb.edu;
Fax: (+01) (805) 893-4120
w This article is part of a ChemComm web-based themed issue on new
advances in catalytic C–C bond formation via late transition metals.
z Electronic supplementary information (ESI) available: experimental
procedure, 1H and 13C NMR spectra, and the X-ray structure of
compound 6a. See DOI: 10.1039/c1cc12212f
Scheme 1 Formation of O-alkenyl-N-phenylhydroxylamines via HO
addition to alkynes en route to indoles.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 7815–7817 7815