DOI: 10.1002/chem.201406305
Communication
&
Heterocycle Synthesis
Pd0-Catalyzed Intramolecular a-Arylation of Sulfones: Domino
Reactions in the Synthesis of Functionalized
Tetrahydroisoquinolines
Daniel Solꢀ,* Ferran Pꢀrez-Janer, and Raffaella Mancuso[a]
further reaction with an electrophile such as a Michael
Abstract: A new strategy for the synthesis of tetrahydro-
isoquinolines based on the Pd0-catalyzed intramolecular
a-arylation of sulfones is reported. The combination of
this Pd-catalyzed reaction with intermolecular Michael and
aza-Michael reactions allows the development of two- and
three-step domino processes to synthesize diversely
functionalized scaffolds from readily available starting
materials.
acceptor.
To test our proposal, we focused on the synthesis of tetra-
hydroisoquinolines, given that this heterocyclic system is
a common structural motif in pharmaceuticals and natural
products.[10] A general approach to this type of compound,
using a tandem palladium-catalyzed a-arylation and Michael
addition strategy, would complement existing methodologies
and in some cases provide a more attractive option.[11,12]
Herein, we report our studies on the intramolecular palladium-
catalyzed a-arylation of b-aminosulfones, and present new
domino processes based on this reaction, which allow the
straightforward synthesis of diversely functionalized tetra-
hydroisoquinolines (Scheme 1).
The sulfone is a ubiquitous organic structural motif that is
often used as an auxiliary group in important synthetic
methodologies, especially those devoted to the formation of
carbon–carbon bonds, in which the sulfonyl group usually acts
as an electron-withdrawing moiety facilitating the deprotona-
tion of a neighboring carbon atom.[1] Moreover, sulfones are
also present in a large number of synthetic biologically active
compounds,[2] as well as in some natural products.[3] Due to
their significance, the development of new and efficient
methods for the synthesis of sulfones is today an interesting
challenge.
Scheme 1. Proposed tandem Pd0-catalyzed a-arylation/Michael addition of
sulfones to access tetrahydroisoquinolines.
In recent years, palladium-catalyzed arylation of acidic CÀH
bonds has received a great deal of attention.[4] However,
despite the popularity of this type of reaction, examples of pal-
ladium-catalyzed a-arylation of sulfones are scarce, probably
due to the higher pKa values of the sulfonyl a-CÀH group, and
they have been limited to intermolecular processes.[5–7]
The first challenge in developing our project was to identify
a suitable combination of base, catalyst, and solvent for the
intramolecular a-arylation of b-aminosulfones. The sulfone 1a
was chosen as a model to optimize the reaction conditions for
the a-arylation (Table 1). The intermolecular a-arylation of
unactivated sulfones usually requires the presence of strong
bases, such as LiN(SiMe3)2 or LiOtBu,[5c–e] but in our case this
was precluded by the retro-Michael degradation of the b-ami-
nosulfone moiety (see below). However, treatment of 1a with
[Pd(PPh3)4] as the catalyst and K3PO4 in DMF at high tempera-
ture, an effective combination for the a-arylation of amino acid
esters,[9e] resulted only in the recovery of the starting material
(Table 1, entry 1). A similar result was obtained when using
1,1’-bis(di-tert-butylphosphino)ferrocene (dtpf) as ligand in-
stead of PPh3 (Table 1, entry 2). The use of the ligand BINAP
(2,2’-bis(diphenylphosphino)-1,1’-binaphthyl; Table 1; Table 1,
entry 3) promoted the total consumption of sulfone 1a to give
a complex reaction mixture, from which the major product, di-
sulfone 3a, was isolated in 22% yield. This compound is
generated by the conjugate addition of the initially formed
a-arylation product 2a to phenyl vinyl sulfone, which arises
from the partial retro-Michael fragmentation of 1a under the
reaction conditions.
As part of our ongoing program on the development of
efficient methodologies for the synthesis of nitrogen hetero-
cycles,[8] we have been studying the palladium-catalyzed
intramolecular coupling of amino-tethered aryl halides with
enolate-type nucleophiles.[9] To further generalize the applica-
tion of the a-arylation reaction to the synthesis of azaheterocy-
cles, we decided to explore the use of sulfones as the nucleo-
philic counterpart. Additionally, we envisaged that the poten-
tial of this palladium-catalyzed reaction could be dramatically
improved if, in one pot, the a-arylation product undergoes
[a] Prof.Dr. D. Solꢀ, F. Pꢀrez-Janer, Dr. R. Mancuso
Laboratori de Quꢁmica Orgꢂnica, Facultat de Farmꢂcia
Universitat de Barcelona
Av. Joan XXIII s/n, 08028 Barcelona (Spain)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406305.
Chem. Eur. J. 2015, 21, 4580 – 4584
4580
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim