Stereoselective synthesis of α-aryl-2-benzofuranmethanamines and α- aryl-1H-indole-2-methanamines through palladium-mediated annulation of chiral α-arylpropargylamines

Article abstract of DOI:10.1016/S0957-4166(00)00131-2

The title compounds, valuable chiral synthons for the synthesis of biologically active compounds, have been prepared in good yield and with high stereoselectivity through palladium-catalyzed heteroannulation of 2- iodophenol or 2-iodo-N-mesylaniline with

Full text of DOI:10.1016/S0957-4166(00)00131-2

Tetrahedron: Asymmetry 11 (2000) 1681±1685
Stereoselective synthesis of a-aryl-2-benzofuranmethanamines
and a-aryl-1H-indole-2-methanamines through palladium-
mediated annulation of chiral a-arylpropargylamines
Flavia Messina,a,y Maurizio Botta,a,* Federico Corellia,* and Claudio Villanib
a
Á
Dipartimento Farmaco Chimico Tecnologico, Universita di Siena, Via A. Moro, 53100 Siena, Italy
b
Á
Dipartimento Scienze del Farmaco, Universita di Chieti `G. D'Annunzio', Via dei Vestini, Chieti Scalo, Chieti, Italy
Received 21 February 2000; accepted 31 March 2000
Abstract
The title compounds, valuable chiral synthons for the synthesis of biologically active compounds, have
been prepared in good yield and with high stereoselectivity through palladium-catalyzed heteroannulation
of 2-iodophenol or 2-iodo-N-mesylaniline with enantiomerically pure or enriched a-arylpropargylamines.
# 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
The transition metal-mediated annulation of alkynes has proven useful for the synthesis of a
variety of hetero- and carbocyclic ring systems.1 Methodology based on palladium is of special
value, since the palladium complexes are readily available, generally not oxygen or moisture sensitive,
and accommodate a number of di€erent functional groups.2 The synthetic potential of palladium-
mediated carbon±carbon bond forming reactions, such as Suzuki, Stille, and Heck couplings, has
been still further enhanced by their successful transfer to the solid-phase environment.3
In connection with our investigations on chiral, non-racemic imidazole compounds as anti-
fungal and antiaromatase agents,4,5 we have recently described the palladium-mediated hetero-
annulation of homochiral arylpropargylic alcohols to give aryl 2-benzofuranyl carbinols 1 and
aryl 2-indolyl carbinols 2 (Fig. 1).6 Pursuing the same research line, herein the ®rst enantio-
selective synthesis of a-aryl-2-benzofuranmethanamine 3 and a-aryl-1H-indole-2-methanamine 4
through the palladium-mediated heteroannulation of chiral, non-racemic arylpropargylamines 57
is reported. Some mechanistic aspects of the heteroannulation reaction are also brie¯y presented.
* Corresponding authors. E-mail: botta@unisi.it and corelli@unisi.it
y
Present address: GlaxoWellcome, Medicines Research Centre, Verona, Italy.
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00131-2

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Figure 1.
Compounds 3 are valuable intermediates for the preparation of homochiral imidazole derivatives
6,8 some of which have been shown to be potent, enantioselective inhibitors of aromatase in vitro.
On the other hand, racemic indolemethanamines 4 have been used as important building blocks
in the synthesis of C-terminal inhibitors of HIV protease.9
2. Results and discussion
Racemic and enantiomerically pure or enriched arylpropargylamines 5 (1.0 mmol) were reacted
with 2-iodophenol (1.0 mmol) in the presence of PdCl2(PPh3)2 (0.025 mmol), CuI (0.025 mmol),
and tetramethylguanidine (TMG, 3.0 mmol) in DMF at 40ꢀC for 16±20 h while passing argon
through the reaction mixture, according to the procedure developed for the corresponding
alcohols, to a€ord the benzofuran derivatives 3 in good yield and with high stereoselectivity.10
Analogously, reaction of 5 with 2-iodo-N-mesylaniline under the same experimental conditions
gave a-aryl-1-methanesulfonyl-1H-indole-2-methanamines 4. Experiments of this nature are
described in Scheme 1 and Table 1.
Scheme 1.
Enantiomeric excesses were determined by HPLC analyses on a chiral column (Chiralcel,
Daicel Chemical Co., Ltd), while the absolute con®gurations were assigned based on those of the
corresponding propargylamines.7 It should be pointed out that the enantiomeric excess of the
resulting product was similar to that of the corresponding starting material: in no case was a loss
of enantiomeric excess higher than 3% observed. Such a high stereospeci®city of the palladium-
mediated annulation is understandable since the stereogenic center of the substrate is not
involved in the probable reaction mechanism outlined in Scheme 2.11

F. Messina et al. / Tetrahedron: Asymmetry 11 (2000) 1681±1685
1683
Table 1
Palladium-mediated cyclization of propargylamines 5 to benzofurans 3 and indoles 4
The mesylation of 2-iodoaniline was crucial for the annulation reaction to occur, since
2-iodoaniline on reaction with propargylamine 5a only gave the coupling product 7 (Fig. 2),
which in turn could not be cyclized to the indole derivative 4a. On the other hand, the inter-
mediate 8, which proved to be resistant to annulation under either palladium or base catalysis,
was smoothly converted to indole 4a by treatment with CuI and TMG in DMF at 40ꢀC. Based on

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F. Messina et al. / Tetrahedron: Asymmetry 11 (2000) 1681±1685
Scheme 2.
these ®ndings, we hypothesize that the heteroannulation step may be copper-catalyzed and,
accordingly, the XH group of the aromatic substrate should be able to coordinate copper
(structure 9) in the presence of CuI and TMG.
Figure 2.
It is interesting to note that, unlike propargylic alcohols, the corresponding propargylamines
have not as yet found very extensive application in palladium-mediated heteroannulation reactions
and, to the best of our knowledge, the reaction reported here is the ®rst example involving
homochiral a-arylpropargylamines.12
Acknowledgements
We thank the Italian CNR and the University of Siena for ®nancial support.
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