Regiocontrolled gold(I)-catalyzed cyclization reactions of N-(3-iodoprop-2-ynyl)-N-tosylanilines

Article abstract of DOI:10.1016/j.jorganchem.2010.09.014

The gold(I)-catalyzed cyclization reactions of N-(3-Iodoprop-2-ynyl)-N- tosylaniline derivatives afford iodinated 1,2-dihydroquinoline derivatives. Two regioisomer products are obtained, one derived from direct cyclization and other involving concomitant

Full text of DOI:10.1016/j.jorganchem.2010.09.014

Journal of Organometallic Chemistry 696 (2011) 12e15
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Communication
Regiocontrolled gold(I)-catalyzed cyclization reactions of N-(3-iodoprop-2-ynyl)-
N-tosylanilines
*
Pablo Morán-Poladura, Samuel Suárez-Pantiga, María Piedrafita, Eduardo Rubio, José M. González
Departamento de Química Orgánica e Inorgánica and Instituto Universitario de Química Organometálica “Enrique Moles”- Unidad Asociada al CSIC, Universidad de Oviedo,
C/Julián Clavería 8, 3306 Oviedo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The gold(I)-catalyzed cyclization reactions of N-(3-Iodoprop-2-ynyl)-N-tosylaniline derivatives afford
iodinated 1,2-dihydroquinoline derivatives. Two regioisomer products are obtained, one derived from
direct cyclization and other involving concomitant 1,2-iodo migration. The ratio of these two products
can be modulated by a proper ancillary ligand in the gold catalyst.
Received 30 July 2010
Received in revised form
2 September 2010
Accepted 3 September 2010
Available online 21 September 2010
Ó 2010 Elsevier B.V. All rights reserved.
Dedicated to the memory of the late
professor José M. Concellón
Keywords:
Gold catalyst
Cyclization
Dihydroquinolines
Ligand effect
1. Introduction
envisaged, as outlined (Eq. (1)). Iodination events that involve
concomitant cyclization or the use of pre-iodinated building blocks
The addition of arenes across alkynes is a powerful transformation
for developing CeC bond-making processes. Its intramolecular
version offers a conceptually attractive entry into a straightforward
assembly of a variety of benzofused skeletons. Thus, mechanistically
diverse metal-catalyzed reactions [1] and even Brønsted or Lewis
acid-catalyzed transformations [2] have been reported. Notably,
connected alkyne activation processes triggered upon the addition of
stoichiometric amounts of a proper iodonium donor represent
a versatile and complementary strategy to selectively access to
related arylated products [3]. Furthermore, current awareness of the
potential of gold-catalyzed organic transformations has a major
impact in the advance of the topic [4].
for the elaboration of the target core, preferably via catalytic
processes, are useful choices [5].
On the other hand, cross-coupling reactions of synthetic
building-blocks based on Csp2-I bonds are well established
synthetic tools associated with contemporary strategies oriented
towards the rapid molecular diversification of a given core. All this
considered, there is a need for advances in fundamental method-
ology aimed at an efficient and selective assembly of key iodinated
frames. For this purpose, besides site-selective iodinations, two
alternatives based on de novo elaboration strategies can be
The potential of iodine to undergo 1,2-migration in metal-
catalyzed cyclizations involving 1-iodo-1-alkynes [6], and
a seminal remark by Fürstner and coworkers on the control of the
regioselectivity in cyclization reactions leading to halophenan-
threne derivatives as a function of the metal catalyst used (Eq. (2))
[7], provide ground to explore the possibility of achieving related
product modulation by an alternative and appropriate ligand
tuning in gold(I)-catalyzed carbocyclization reactions leading to
heterocyclic scaffolds.
* Corresponding author. Tel.: þ34 985 10 2980.
E-mail address: jmgd@uniovi.es (J.M. González).
0022-328X/$ e see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2010.09.014

P. Morán-Poladura et al. / Journal of Organometallic Chemistry 696 (2011) 12e15
13
Scheme 2. Proposed rationalization for the observed manifold of cycloisomerization
products in gold(I)-catalyzed cyclizations of N-(3-iodoprop-2-ynyl)-N-tosylaniline 1a.
Now, we disclose preliminary results on the feasibility of such
an expectation.
The outcome of these experiments provides support to the
hypothesis of affecting the product distribution in gold (I)-cata-
lyzed hydroarylation reactions involving iodoalkynes by ligand
tuning. The direct cyclization is favoured by the use of the phos-
phite ligand that would drive the classic cyclization as a result of
the electrophilic nature of the gold centre, resulting in the forma-
tion of the cyclization product 2a. On the contrary, the catalyst
based on IPr ligand, that is strong donor to the metal, comparatively
favours the 1,2-iodine shift that would switch the nature of the
intermediate to a vinylidine species that, eventually, would render
product 3a. For a tentative draft that justify the formation of the
observed 1,2-dihydroquinoline derivatives in a graphical manner,
see Scheme 2. Their structures were drawn on the basis of detailed
nmr spectroscopic studies. Also, the structure of 3a was unambig-
uously confirmed by X-ray diffraction analysis [13].
The metal-control over product distribution early documented
for the elaboration of halophenanthrenes [7] implicates substrates
in which the arylating ring is an electron-rich one that, in general,
has been considered a requirement for gold-catalyzed cyclizations
involving hydroarylation reactions. For this reason, it would be of
interest to begin the exploration of the versatility and constrains
associated with the cyclization now being reported. Importantly, it
could be reasonably anticipated that the nature of the substituents
of the arene ring would also play a key role to determine the nature
of the cyclization mixture. So, research to broach the efficiency and
the subtleness behind this process were conducted and the most
relevant results are now presented (Table 1).
2. Results and discussion
On the ground of all of the above discussed and keeping in mind
the inherent interest associated with the so-called privileged
structures in medicinal chemistry [8] we choose N-(3-iodoprop-2-
ynyl)-N-tosylaniline as a useful model compound. In terms of the
catalyst, chloride and bis(trifluoromethanesulfonyl)imidate (NTf2)
gold(I) complexes were selected. As Gagosz recognized, the latter
counter anion behaves similar to other weakly coordinating anions
and does not require the addition of a silver (I) salt to render an
electrophilic gold centre [9]. Concerning the selection of the ligand
intended to be responsible for the control of the selectivity, and
considering the multiple options existent, this work is focused on
the investigation of the reactivity of two limit systems to try to
access cationic gold centres with significantly differentiated elec-
tron density [10]. Specifically, attention was paid to gold complexes
derived from either the bulky tris(2,4-di-tert-butylphenyl)phos-
phite and the N-heterocyclic carbene ligand IPr [IPr: 1,3-bis(2,6-
diisopropyl)phenylimidazol-2-ylidene] [11].
In the initial trials [12], the transformations were performed
under argon atmosphere, at room temperature (c.a. 20 ꢀC) for
a period of 24 h. The reactions were conducted using 0.3 mmol of
the starting alkyne (0.15 M solutions in dichloroethane), and the
load of the catalytic system (ArO)3PAuCl/AgBF4 (1:1 ratio) (I) or
IPrAuNTf2 (II) was kept at 3 mol.
The aniline derivative 1a was exposed to both catalytic systems
and the main findings are depicted in Scheme 1.
Table 1
Entry
Substrate 1
Catalysta
Global yieldb (%)
Ratioc 2:3
1
2
3
4
5
6
7
8
9
1b (R: Me)
1b (R: Me)
1c (R: OMe)
1d (R: I)
I
(98)
75 (99)
81
52
79
7.9:1
1:4.8
1:1.5
1:70
1:2.2
<1:99<
II
II
II
I
II
II
I
1e (R: Cl)d
1e (R: Cl)
80
e
1f (R: NO2)d
1g (R: COMe)
1g (R: COMe)
67
72
3.5:1
1:23
II
a
For the catalyst structure, see Scheme 1.
b
c
Isolated yields; within brackets, yields estimated by nmr.
Calculated by nmr.
The reactions were carried out at 80 ꢀC.
Scheme 1. Exploratory trial proving the ligand influence over a gold(I)-catalyzed
cyclization of N-(3-iodoprop-2-ynyl)-N-tosylaniline 1a.
d

14
P. Morán-Poladura et al. / Journal of Organometallic Chemistry 696 (2011) 12e15
Scheme 3. IPrAuNTf2-catalyzed cyclization of N-(3-iodoprop-2-ynyl)-N-tosyl-1-naphthylamine derivative 1h.
The data in Table 1 clearly evidence a modulation of the nature
affords predominantly the cyclization product incorporating the
iodine migration in the structure of the major isomer.
of the reaction products by both, the ancillary ligand on the cata-
lytic system and the substituent onto the substrate that becomes
part of the metal systems upon coordination. Again, for a given
substrate 1, catalyst II gives always lower 2:3 ratios, favouring the
formation of the corresponding cyclization product 3 arising from
a 1,2-iodine shift (entries 1/2; 5/6 and 8/9). An additional experi-
ment was conducted to scrutinize the possibility of a major coun-
terion effect also operating [14]. Thus, 1b was also subjected to
reaction with the alternative catalytic system resulting from the
AgBF4 activation of the IPrAuCl complex. When 1b was exposed,
under argon atmosphere, to 3 mol% of this catalytic system, in DCE
at room temperature for 21 h, complete consumption of the start-
ing iodoalkyne and the formation of a 1:5 ratio of 2b:3b in 99%
overall yield was noticed (calculated by nmr using 1,3,5-trime-
thoxybenzene as inner reference). The outcome of this experiment
is in line with the previous result obtained using IPrAuNTf2 as
catalyst and suggests that for this transformation, the counterion is
not significantly affecting the observed product distribution.
On the other hand, the use of a substrate 1 having a more elec-
tron-rich arene speeds comparatively the direct cyclization leading
to 2, thus hampering the formation of product 3 derived from a pre-
organization of the system via 1,2-migration [15]. So, for instance,
using the catalyst II, the relative amount of compound 3 diminished
in going from simple phenyl to 4-methoxyphenyl, with an inter-
mediate figure for the tolyl derivative (see Scheme 2 and Table 1
entries 3 and 2, respectively). Significantly, this process is also
compatible with the presence of moderately deactivating groups
though, so far, the cyclization is inhibited when a strong-deacti-
vating nitro group is present. Regarding the selectivity, the presence
of electron-withdrawing groups should slow the direct cyclization
process, allowing for the iodine migration to occur. In fact, excellent
selectivity in favour of the formation of the corresponding product 3
was noticed in those cases (see entries 4, 6 and 9).
Further work devoted to improve the efficiency, scope and some
practical issues concerning the synthetic potential of the herein
sketched new transformation are in progress. Among them are
research efforts addressing solvent and temperature effects and
other factors that might affect the selectivity. Also further ligand
optimization studies and work aimed at the eventual imple-
mentation of this chemistry to prepare other hetero and carbo-
cycles in a related manner will be undertaken.
3. Conclusions
In short, initial exploratory studies and conceptual basis for
a
new protocol to access differently site-iodinated relevant
heterocyclic frames are reported. This product diversity is accessed
by judicious ligand tuning in gold (I)-catalyzed intramolecular
hydroarylation reactions involving simple tethered iodoalkynyl and
arene partners.
Acknowledgements
We are grateful to the MICINN/FEDER (Grant CTQ-2007-61048)
and the Principado de Asturias (Grant IB 08-088). S.S.-P. and M.P.
thank the Ministerio de Educación and the European Union (Fondo
Social Europeo) for a predoctoral fellowship. We thank the
reviewers for their useful suggestions.
Appendix. Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.jorganchem.2010.09.014.
References
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