Isoindoles and dihydroisoquinolines by gold-catalyzed intramolecular hydroamination of alkynes

Article abstract of DOI:10.1039/b516017k

The title compounds are enantioselectively synthesized in just two prepararative steps, making use of the Ugi-four-component reaction with an amino acid as chiral component, followed by a gold-catalyzed hydroamination. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b516017k

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Isoindoles and dihydroisoquinolines by gold-catalyzed intramolecular
hydroamination of alkynes
Daniel Kadzimirsz, Dirk Hildebrandt, Klaus Merz and Gerald Dyker*
Received (in Cambridge, UK) 11th November 2005, Accepted 19th December 2005
First published as an Advance Article on the web 12th January 2006
DOI: 10.1039/b516017k
complexes exhibit a high reactivity as rather soft Lewis-acids,
especially in terms of alkyne activation for nucleophilic attacks,2
enabling these processes to proceed under very moderate reaction
conditions. As part of our ongoing studies on gold-catalyzed
annelation reactions3 we envisioned that a two step sequence of the
Ugi-four-component reaction4 with a gold-catalyzed cyclization
should offer a fascinating opportunity to build up chiral
heterocycles with a high degree of complexity.
The title compounds are enantioselectively synthesized in just
two prepararative steps, making use of the Ugi-four-component
reaction with an amino acid as chiral component, followed by a
gold-catalyzed hydroamination.
Gold-catalyzed reactions have emerged as powerful and highly
selective tools for organic synthesis in recent years:1 obviously gold
According to this general idea we applied L-valine (1) as chiral
amine component and benzaldehydes 45 as source of the alkyne
moiety. The condensation process of the four reaction components
1–4 proceeds somewhat sluggishly at room temperature within 6 to
9 days, building up the highly functionalized amines 5, finally with
satisfactory yield and diastereoselectivity (Scheme 1).
The hydroamination6 succeeded with just 3 mol-% gold chloride
as catalyst in acetonitrile at 80 uC with overall yields above 70%:
the dihydroisoquinolines 7 obviously are the result of a 6-endo-dig
cyclization, whereas the isoindoles 8 derive from the 5-exo-dig
products 6, which of course isomerize under aromatization under
the acidic reaction conditions.
Alkynes 5 were applied as purified main diastereomers and gave
7a and 7b as single diastereomers according to TLC and NMR,
thus indicating configurational stability under the acidic reaction
conditions. In crystals of 7b there are two independent molecules
with identical configurations in the unit cell. Knowing the absolute
configuration of the L-valine chiral centres to be S our X-ray
structure analysis of 7b (Fig. 1) then established that the other
chiral centres have the R-configuration.7
To our knowledge 8a and 8b are the first examples of chiral
isoindoles, prompting us to test the face selectivity of the Diels–
Alder reaction of 8b with acetylene dicarboxylic acid dimethyl ester
Scheme 1 Combination of Ugi reaction, hydroamination and Diels–
Alder reaction.
Fakulta¨t fu¨r Chemie, Ruhr-Universita¨t Bochum, Universita¨tsstrasse 150,
D-44780, Bochum, Germany. E-mail: Gerald.Dyker@rub.de;
Fax: +49 (0)234/32-14353; Tel: +49 (0)234/32-24551
Fig. 1 Structure of the chiral isoquinoline 7b in the crystal.
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9. As the result we obtained a 3 : 1 mixture of the diastereomers of
10b as an oily product: further separation and purification failed
because of partial decomposition during flash chromatography. In
test tube experiments also the Diels–Alder reactions with N-methyl
and N-4-tolyl maleimides were examined: the resulting cycload-
ducts were even more sensitive than 10b, clearly undergoing retro-
Diels–Alder reaction at room temperature on silica. The retro
reaction obviously profits from the electronic stabilization of
isoindoles 8 by the amide substituent, which is part of the
conjugated donor–acceptor system with the isoindole nitrogen.
Normally retro-Diels–Alder reactions of isoindole adducts take
place at much more elevated temperatures.8
In summary, the combination of Ugi reaction and gold catalysis
offers a valuable opportunity for building up chiral dihydroiso-
quinolines and isoindoles, which are highly functionalized and of
interest for further stereoselective transformations.
We gratefully acknowledge financial support from Fonds der
Chemischen Industrie and the Deutsche Forschungsgemeinschaft
(DFG-project DY 12/7-2).
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2000, 19, 170; (b) E. Mizushima, T. Hayashi and M. Tanaka, Org. Lett.,
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Notes and references
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2 Current examples of gold catalyzed reactions of alkynes: (a) Y. Luo and
C. J. Li, Chem. Commun., 2004, 1930; (b) Z. Shi and C. He, J. Am. Chem.
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Smith and F. D. Toste, Angew. Chem., Int. Ed., 2004, 43, 5350; (d) X. Yao
and C.-J. Li, J. Am. Chem. Soc., 2004, 126, 6884; (e) A. S. K. Hashmi,
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7 G. M. Sheldrick, SHELXTL-97, University of Go¨ttingen, 1997. Crystal
data for 7b: C26H32N2O3, M = 420.54, triclinic, space group P1, a =
˚
9.187(14), b = 11.389(18), c = 12.80(2) A, a = 105.30(13), b = 93.62(10),
3
˚
c = 105.23(8)u, V = 1234(3) A , Z = 2, 2hmax = 50u, 5711 measured
reflections, 512 parameters, m = 0.074 mm21, R1 = 0.0509 for 2835
observed reflections (I > 2s(I)), wR2 = 0.1214 for all reflections; The
intensity data were collected on a Bruker-axs-SMART 1000 diffract-
˚
ometer (Mo-Ka radiation, l = 0.71707 A, T = 203 K). The structure was
solved by direct methods and refined by full matrix least squares using
SHELXTL-97. All non-hydrogen atoms were refined using anisotropic
thermal parameters; hydrogen atoms were included by use of a riding
model and fixed isotropic thermal parameters. CCDC 289676. For
crystallographic data in CIF or other electronic format see DOI: 10.1039/
b516017k.
8 (a) P. Sohar, F. Miklos, A. Csampai and G. Stajer, J. Chem. Soc., Perkin
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662 | Chem. Commun., 2006, 661–662
This journal is ß The Royal Society of Chemistry 2006