Gold(i)-catalyzed formation of dihydroquinolines and indoles from N-aminophenyl propargyl malonates

Article abstract of DOI:10.1039/c0cc00033g

The use of [XPhosAu(NCMe)]SbF₆ in nitromethane at 100 °C allows the rapid and efficient formation of variously substituted dihydroquinolines, which can be subsequently converted into indoles by a rare photochemical rearrangement.

Full text of DOI:10.1039/c0cc00033g

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Gold(I)-catalyzed formation of dihydroquinolines and indoles
from N-aminophenyl propargyl malonateswz
Colombe Gronnier, Yann Odabachian and Fabien Gagosz*
Received 19th February 2010, Accepted 26th March 2010
DOI: 10.1039/c0cc00033g
The use of [XPhosAu(NCMe)]SbF6 in nitromethane at 100 1C
allows the rapid and efficient formation of variously substituted
dihydroquinolines, which can be subsequently converted into
indoles by a rare photochemical rearrangement.
Gold catalysis has proven during the last decade to be a
powerful synthetic tool for the synthesis of a large variety
of nitrogen containing heterocycles.1 Among the different
strategies employed, those based on the use of an intramolecular
gold-catalyzed hydroarylation reaction are particularly attractive
as they allow the easy creation of a new C–C bond by the
nucleophilic addition of an aryl unit onto an insaturation.2
This approach has been applied for instance to the formation
of dihydroquinolines 3 by a gold-catalyzed 6-endo cyclization
of N-propargyl anilines 1 (Scheme 1, n = 1).3
Following our own interest in gold catalysis, we wondered if
the homologous N-butynyl anilines 2 might be valuable
substrates for the synthesis of the isomeric exo-methylene
tetrahydroquinolines 4 via, in this case, a 6-exo cyclization
(Scheme 1, n = 2). N-Butynyl tosylaniline 5a, was first chosen
as a model substrate for this study (Scheme 2).3a,b However,
no cyclized product 7a could be observed in this case whatever
the catalyst, the solvent or the temperature used.4 The
transformation was next attempted with substrate 5b where
the aryl moiety is more nucleophilic. An encouraging 11%
yield of 7b was obtained when the reaction was conducted in
Scheme 2 Preliminary studies.
nitromethane at 100 1C with [XPhosAu(NCMe)]SbF6 (6) as
the catalyst.5 Aniline derivative 8, proved to be a more useful
products namely exo-methylene tetrahydroquinoline 9 and
dihydroquinoline 10 in a 2 : 1 ratio (Scheme 2).6,7
substrate since its treatment with 1 mol% of 6 in nitromethane
at 100 1C for 1.5 h led to the formation of two cyclized
Subsequent treatment of the crude reaction mixture with
p=TsOH (5 mol%) led to the rapid isomerization of 9 into 10,
which was finally isolated in 92% yield.8 The reaction could
also be efficiently performed (99%) on a 5 mmol scale with
a reduced loading of catalyst (0.5 mol%). Under these
conditions and by carefully monitoring the reaction, it was
even possible to suppress the formation of isomeric compound
10. The presence of the malonate moiety in substrate 8 appears
to be crucial for the efficient formation of the hydroarylation
product. The replacement of the esters of the malonate moiety
by two acetoxymethyl groups (substrate 12) had a negative
effect, as only 5% of the corresponding hydroarylation
product was produced after 3 h of reaction.9 Dihydroquinoline
10 was not very stable, and we were surprised to observe its
slow conversion into indole 11 when a chloroform solution of
10 was exposed to sunlight (Scheme 2).10,11
Scheme 1 Au-mediated synthetic approaches to hydroquinolines.
Laboratoire de Synthe`se Organique, UMR 7652 CNRS/Ecole
Polytechnique, Ecole Polytechnique, 91128 Palaiseau, France.
E-mail: gagosz@dcso.polytechnique.fr
w This article is part of the ‘Emerging Investigators’ themed issue for
ChemComm.
This unexpected photochemical rearrangement is particularly
interesting since indole 11 could be formed in high yield in
only two steps from the readily available N-aminophenyl
propargyl malonate 8.
z Electronic supplementary information (ESI) available: Experimental
procedures and spectra. See DOI: 10.1039/c0cc00033g
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Table 1 Scope of the hydroarylation processa
a
Reaction conditions: step 1: 14 (1 equiv.), [XPhosAu(NCMe)]SbF6 (6) (0.01 equiv.) in refluxing CH3NO2 (1 M); step 2: p-TsOH (0.05 equiv.) in
CH2Cl2 (0.1 M) at rt or reflux. b Reaction time for step 1. c Determined by 1H NMR spectroscopy of the crude reaction mixture after step 1.
d Isolated yields after step 2. e 6 (2 mol%). f Yield of exo-methylene compound 15. Isomerization was incomplete. g Global yield of the isomeric
mixture (16 + 160).
A series of diversely substituted N-aminophenyl propargyl
malonates 14a–t were then synthesized4 and reacted under
the same reaction conditions (1 mol% of 6 in nitromethane
at 100 1C) to determine the scope of the hydroarylation
process. The results of this study are compiled in Table 1.
The transformation proved to be efficient and various
dihydroquinolines 16a–t were rapidly obtained in yields
ranging from 53 to 99%. The gold catalyzed hydroarylation
process selectively furnished the exo-methylene compounds 15
with the exception of substrates 14b–d, which resulted in
isomeric mixtures of 15b–d and 16b–d (entries 2–4). In the
case of the electron rich substrates 14o and 14p (entries 15
and 16), the gold catalyzed process directly produced the
corresponding dihydroquinolines 16o and 16p, as the result
of a more favourable gold-catalyzed isomerization of the
exo-methylene. Various substitutents on the nitrogen atom
such as an alkyl group (entry 1), a phenyl ring (entry 2) or a
cycloalkyl unit linked to the aromatic ring (entries 3 and 4)
were tolerated. The reaction was also compatible with a wide
range of functional groups onto the aromatic ring such as an
electron donating ether group (entries 5–7, 15, 16 and 18), a
halogen atom (entries 8–11 and 14), or an electron withdrawing
ester (entry 12), cyano (entry 13) or trifluoromethyl (entry 20)
group. Notably, the efficiency and the rapidity of the
reaction were not markedly dependent on the electronic
nature of the substituent (compare entries 5–13) or its position
on the aromatic ring since ortho (entries 3, 4 and 14),
meta (entries 15–20) or para (entries 5–13) substituted aryl
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Notes and references
1 Recent reviews: (a) A. Furstner, Chem. Soc. Rev., 2009, 38, 3208;
¨
(b) P. Belmont and E. Parker, Eur. J. Org. Chem., 2009, 6075;
(c) V. Michelet, P. Y. Toullec and J. P. Genet, Angew. Chem., Int.
Ed., 2008, 47, 4268; (d) A. S. K. Hashmi and M. Rudolph, Chem.
Soc. Rev., 2008, 37, 1766; (e) E. Jimenez-Nu´ nez and
´
A. M. Echavarren, Chem. Rev., 2008, 108, 3326; (f) Z. Li,
C. Brower and C. He, Chem. Rev., 2008, 108, 3239;
(g) A. Arcadi, Chem. Rev., 2008, 108, 3266; (h) D. J. Gorin and
F. D. Toste, Chem. Rev., 2008, 108, 3351; (i) R. Skouta and
C.-J. Li, Tetrahedron, 2008, 64, 4917.
2 Selected articles: (a) M. A. Tarselli and M. R. Gagne, J. Org.
Chem., 2008, 73, 2439; (b) I. V. Seregin, A. W. Schammel and
V. Gevorgyan, Org. Lett., 2007, 9, 3433; (c) T. Watanabe, S. Oishi,
N. Fujii and H. Ohno, Org. Lett., 2007, 9, 4821; (d) N. Marion,
S. Dıez-Gonzalez, P. de Fremont, A. R. Noble and S. P. Nolan,
´ ´ ´
Angew. Chem., Int. Ed., 2006, 45, 3647; (e) C. Ferrer and
A. M. Echavarren, Angew. Chem., Int. Ed., 2006, 45, 1105;
(f) Z. Liu, A. S. Wasmuth and S. G. Nelson, J. Am. Chem. Soc.,
2006, 128, 10352; (g) D. J. Gorin, P. Dube and F. D. Toste, J. Am.
Chem. Soc., 2006, 128, 14480; (h) Z. Zhang, C. Liu, R. E. Kinder,
X. Han, H. Qian and R. A. Widenhoefer, J. Am. Chem. Soc., 2006,
Scheme 3 Photochemical rearrangement to indoles.
substrates reacted equally well. While compounds 14o–q,
possessing two substituents at the meta and para positions of
the aniline moiety only produced dihydroquinolines 16o–q
(entries 15–17), the reaction proved to be completely unselective
in the case of substrates 14r–t (entries 18–20).12 The trans-
formation could also be applied with the same efficiency to
substituted alkyne 14u (eqn (1)). The selectivity of the reaction
was complete as the result of an anti addition of the nucleo-
philic aryl moiety onto the gold-activated alkyne.
128, 9066; (i) V. Mamane, P. Hannen and A. Furstner, Chem.–Eur.
¨
J., 2004, 10, 4556; (j) Z. Shi and C. He, J. Org. Chem., 2004, 69,
3669.
3 Selected articles: (a) A. S. K. Hashmi, L. Schwarz, J.-H. Choi and
T. M. Frost, Angew. Chem., Int. Ed., 2000, 39, 2285; (b) C. Nevado
and A. M. Echavarren, Chem.–Eur. J., 2005, 11, 3155;
(c) R. S. Menon, A. D. Findlay, A. C. Bissember and
M. G. Banwell, J. Org. Chem., 2009, 74, 8901; (d) F. Xiao,
Y. Chen, Y. Liu and J. Wang, Tetrahedron, 2008, 64, 2755;
(e) X.-Y. Liu, P. Ding, J.-S. Huang and C.-M. Che, Org. Lett.,
2007, 9, 2645. See also; with Ag catalysis: (f) Y. Luo, Z. Li and
C.-J. Li, Org. Lett., 2005, 7, 2675; with Fe catalysis:
(g) K. Komeyama, R. Igawa and K. Takaki, Chem. Commun.,
2010, 46, 1748; with Lewis-acid catalysis: (h) T. Ishikawa,
S. Manabe, T. Aikawa, T. Kudo and S. Saito, Org. Lett., 2004,
6, 2361.
4 See ESIz for more details.
5 For the use of catalyst 6 in CH3NO2, see: I. D. Jurberg,
Y. Odabachian and F. Gagosz, J. Am. Chem. Soc., 2010, 132,
3543.
ð1Þ
We finally turned our attention to the rearrangement of the
dihydroquinolines into the corresponding indoles, as initially
observed for compound 10. A series of dihydroquinolines were
indeed similarly converted into the corresponding indoles
20a–d by simple exposure to sunlight (67–88%). A mechanism
for this remarkable ring contraction is proposed in Scheme 3.
Upon irradiation, dihydroquinoline 17 undergoes presumably
an electrocyclic ring opening leading to intermediate 18. A
subsequent nucleophilic attack of the nitrogen atom onto the
electrophilic alkylidene malonate moiety, energetically driven
by the re-aromatisation of the benzene ring, furnishes a
zwitterionic species 19 which finally collapses into indole 20.13
In summary, we have developed an efficient synthesis of
exo-methylene tetrahydroquinolines and dihydroquinolines
from readily accessible N-aminophenyl propargyl malonates.
The hydroarylation process, which could be performed with a
low loading of catalyst (1 mol%), proved to be rapid and
general allowing the presence of a plethora of functional groups
on the aromatic ring. Furthermore, the dihydroquinolines
were shown to easily rearrange to functionalized indoles
under photochemical conditions thus expanding the general
synthetic utility of the approach.
6 The use of catalyst 6 in CH3NO2 appears to be the catalytic system
of choice as it stabilizes the catalyst and leads to a rapid and
generally selective formation of 15 for the series of substrates
studied.
7 The 9 : 10 ratio slowly evolves upon prolonged reaction time. For
this alkene isomerisation, see: A. S. K. Hashmi, M. C. Blanco,
E. Kurpejovic, W. Frey and J. W. Bats, Adv. Synth. Catal., 2006,
348, 709.
8 Dihydroquinoline 10 was unstable in the presence of silica.
A simple basic work-up followed, if necessary, by a rapid filtration
through a pad of silica was used to obtain the product in pure
form.
9 The malonate moiety plays multiple roles in this transformation: it
induces a Thorpe–Ingold effect resulting in a more favorable
cyclization while limiting the coordination of the gold catalyst
with the nitrogen atom probably through steric and electronic
effects.
10 The electrocyclic ring-opening of 1,2-dihydroquinolines is a rare
process, see: (a) M. Ikeda, S. Matsugashita, H. Ishibashi and
Y. Tamura, J. Chem. Soc., Chem. Commun., 1973, 922;
(b) M. Ikeda, S. Matsugashita, F. Tabusa, H. Ishibashi and
Y. Tamura, J. Chem. Soc., Chem. Commun., 1974, 433;
(c) M. Ikeda, S. Matsugashita, F. Tabusa and Y. Tamura,
J. Chem. Soc., Perkin Trans. 1, 1977, 1166.
11 No reaction took place under thermal conditions (toluene, 110 1C)
or in the presence of a Lewis acid (Yb(OTf)3, rt). Compound 10
was stable in the absence of light.
12 The hydroarylation seems to be little influenced by the electronic
nature or the steric hindrance of a meta substituent.
13 Formation of 20 may also be explained by the intermediate
formation of an allenylidene malonate from 18 (see ref. 10).
This work was supported by the CNRS and Ecole
Polytechnique. The authors thank Prof. S. Z. Zard for helpful
discussions.
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This journal is The Royal Society of Chemistry 2011
220 | Chem. Commun., 2011, 47, 218–220