Synthesis of furoquinolines by a one-pot multicomponent cascade reaction catalyzed by platinum complexes

Article abstract of DOI:10.1002/chem.200802146

The synthesis of furanquinoline derivatives by one-pot multicomponent cascade reaction with platinum complex, has been reported. The synthesis of spirofuranquinoline derivatives was carried out by using N-arylaldimines and exocyclic enol ethers, while platinum complex and Bronsted acid used as catalysts. It was found that cationic platinum complexes were appropriate catalysts for the in situ formation of enol ethers by intramolecular hydroalkoxylation reactions. This process also demonstrated one-pot three-component coupling reaction between a unit of an alkynol derivative and two units of N-arylaldimine. It was observed that this synthesis process can improve the functionalization of the furan ring and leads to diastereomerically pure furoquinoline derivatives. This process can be used for the synthesis of potentially bioactive compounds.

Full text of DOI:10.1002/chem.200802146

DOI: 10.1002/chem.200802146
Synthesis of Furoquinolines by a One-Pot Multicomponent Cascade Reaction
Catalyzed by Platinum Complexes
Josꢀ Barluenga,* Abraham Mendoza, Fꢀlix Rodrꢁguez, and Francisco J. FaÇanꢂs[a]
Tetrahydroquinolines have been found as a key structural
unit in many bioactive natural products and pharmaceuti-
cals.[1] In particular, furoquinoline derivatives are alkaloids
mainly isolated from Rutaceae and Solanaceae plant spe-
cies.[2] Owing to the relevant biological properties of both
natural and synthetic analogues of these molecules,[3] which
include antitumoral, antimicrobial, antibacterial, insecticide,
analgesic, antipyretic, antiplatelet, and cytotoxic activities,
the isolation and synthesis of new furoquinoline derivatives
is an active and rewarding research area.[4] In this connec-
tion, the Povarov reaction is a powerful transformation that
offers an easy entry to the furoACTHNUGRTNEUNG[3,2-c]quinoline skeleton
Scheme 1. Two different quinoline derivatives obtained from alkynols
and N-arylaldimines.
through a formal [4+2] cycloaddition between N-arylaldi-
mines (as diene) and 2,3-dihydrofuran (as dienophile).[5]
One of the main limitations of this reaction stems from the
enol ether counterpart, since very few functionalized 2,3-di-
hydrofuran derivatives are available. In fact, the great ma-
inum-catalyzed three-component coupling reaction that
allows the easy and diastereoselective synthesis of function-
alized furoquinoline derivatives (Scheme 1),[8] and details of
this process are given herein.
jority of the furoACHTUNGTRENNUNG[3,2-c]quinoline derivatives synthesized by
this strategy are derived from the commercially available
2,3-dihydrofuran and basically no effort has been directed to
the synthesis and study of the biological activity of furoACTHNUTRGNEU[GN 3,2-
As previously reported,[7] cationic platinum complexes
were appropriate catalysts for the in situ formation of enol
ethers by intramolecular hydroalkoxylation reactions. In
that work the cationic platinum catalyst was formed from
[(cod)PtMe2] (cod=1,5-cyclooctadiene) by treatment with a
protic acid. Another possibility for the in situ generation of
the cationic platinum complex is the treatment of
[(cod)PtCl2] with a silver salt under nonacidic conditions.
Accordingly, in an initial experiment we treated pentynol
derivative 1a with two equivalents of the imine 2a in the
presence of a cationic platinum complex generated in situ
by mixing 5 mol% of [(cod)PtCl2] and 10 mol% of AgSbF6.
This reaction led to a 3:1 mixture of the spirofuranquinoline
c]quinoline derivatives substituted at the furan ring. In this
context, we thought that an easy entry to this kind of com-
pounds could be a Povarov reaction[6] in which a functional-
ized furan was generated in situ from an alkynol derivative
by a cycloisomerization reaction. Thus, we have recently re-
ported a new synthesis of spirofuranquinoline derivatives by
reaction of in situ generated N-arylaldimines and exocyclic
enol ethers in a process in which a platinum complex and a
Brønsted acid are used as catalysts (Scheme 1).[7] Further
studies in this field led us to discover an unprecedented plat-
derivative 3a and the furoACTHNURGTNE[UNG 3,2-c]quinoline 4a (Table 1,
entry 1). Bearing in mind our previous results,[7] the forma-
tion of compound 3a, as a mixture of two diastereoisomers,
could be considered as expected. Much more surprising was
the isolation of the styryl-substituted furoquinoline 4a. The
formation of this compound supposes the coupling of three
components, a unit of the alkynol 1a and two units of the
imine 2a, in a process in which a molecule of 4-methoxyani-
line is delivered. Moreover, furoquinoline 4a was formed as
[a] Prof. Dr. J. Barluenga, A. Mendoza, Dr. F. Rodrꢀguez,
Dr. F. J. FaÇanꢁs
Instituto Universitario de Quꢀmica Organometꢁlica “Enrique Moles”
Unidad Asociada al CSIC, Universidad de Oviedo
Juliꢁn Claverꢀa 8, 33006 Oviedo (Spain)
Fax : (+34)985103450
E-mail: barluenga@uniovi.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802146.
10892
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 10892 – 10895

COMMUNICATION
Table 1. Platinum-catalyzed reaction of alkynol 1a and imine 2a under
different conditions.
Entry Equiv 2a Additive
Conditions
standard[b]
Ratio 3a:4a[a]
1
2
3
4
5
2
2
4
4
2
none
3:1
>20:1
1:2
HBF4 (1 equiv)[c] standard[b]
none
none
none
standard[b]
slow addition[d]
slow addition[d]
1:>20
1:1
[a] Determined by 1H NMR analysis of the crude reaction mixture.
[b] All reagents mixed at room temperature and the reaction mixture
was stirred for 24 h. [c] Reagents mixed at À308C. [d] Alkynol 1a slowly
added to a solution of imine 2a and the catalyst over a period of 7 h at
room temperature. The reaction mixture was stirred for an additional
17 h.
a single diastereoisomer and remarkably, a quaternary ste-
reocenter is generated. All these interesting structural fea-
tures led us to consider the possibility of steering the reac-
tion toward the formation of the vinyl-substituted furoqui-
noline 4a. Thus, we tried the reaction under different condi-
tions. We observed that the addition of one equivalent of
the protic acid HBF4 led to the exclusive formation of the
spirofuranquinoline 3a (Table 1, entry 2). In contrast, the
amount of compound 3a was decreased by the addition of
an excess (4 equiv) of the starting imine 2a (Table 1,
entry 3). In particular, formation of compound 3a was prac-
tically suppressed by the slow addition, over a period of 7 h,
of the alkynol 1a to a solution of the imine 2a and the cata-
lyst (Table 1, entry 4). However, using the slow addition
conditions but reducing the amount of imine 2a to two
equivalents, led to a 1:1 mixture of 3a and 4a (Table 1,
entry 5). Thus, we have suitable conditions to direct the re-
action to the formation of the spirofuranquinoline 3a (by
adding a protic acid) or to the vinyl-substituted furoquino-
line 4a (by using a fourfold excess of the starting imine 2a
under slow addition conditions).
As previously mentioned, the structure of the vinyl-substi-
tuted furoquinoline 4 is very attractive and thus the sub-
strate generality was examined under the optimized condi-
tions. Various kinds of alkynols 1 and imines 2 were tested,
and, as shown in Scheme 2, several vinyl-substituted furoqui-
noines 4 were synthesized and isolated in high yield and as
single diastereoisomers in all cases attempted. Structural as-
signments of these new compounds were based on a series
of NMR studies. Additionally, the structure of compound 4i
was confirmed by single-crystal X-ray diffraction analysis.[9]
Those products containing fluorine atoms in their structure
(4b,d,g) may prove to be particularly interesting, and the
chlorine-substituted products 4c,f,h,i could be interesting
Scheme 2. Furoquinolines 4 obtained by a catalytic three-component cou-
pling reaction.
for further functionalization by well-established carbon–
carbon couplings. The furoquinolines 4h,i are also remark-
able as they are derived from a chiral alkynol derivative. In
these cases, we only observed the formation of a single dia-
stereoisomer corresponding to those structures shown in
Scheme 2. These results indicate that the substrate-con-
trolled synthesis of enantiomerically pure furoquinoline de-
rivatives 4 is possible.
A catalytic mechanism that explains the formation of fu-
roquinolines 4 is shown in Scheme 3 (for simplicity substitu-
ents on the alkynol derivative 1 and the imine 2 are not con-
sidered). In this reaction, we suppose the formation of a re-
active cationic platinum complex from [(cod)PtCl2] by reac-
tion with AgSbF6.[10] The reaction is initiated by coordina-
tion of the metallic complex to the triple bond of the
starting alkynol 1 to form intermediate 5. Intramolecular ad-
dition of the hydroxy group to the internal carbon of the
Chem. Eur. J. 2008, 14, 10892 – 10895
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10893

J. Barluenga et al.
c]quinoline derivatives. The reaction is very straightforward,
the starting materials are simple, and the products obtained
cannot be easily synthesized by other methods. The new
process supposes a one-pot three-component coupling reac-
tion between a unit of an alkynol derivative and two units
of an N-arylaldimine. Formally, the reaction could be con-
sidered a Povarov reaction in which the enol ether counter-
part is generated in situ. This strategy allows the functionali-
zation of the furan ring and leads to diastereomerically pure
furoquinoline derivatives, thereby surpassing some of the
limitations of the conventional Povarov reaction. Moreover,
the presence of a vinyl moiety in the final products would
allow further functionalization. The easy generation of mo-
lecular diversity coupled with the importance of furoquino-
line derivatives in medicinal chemistry makes the reaction
described herein an appropriate alternative for the synthesis
of potentially bioactive compounds.
Scheme 3. Mechanism of formation of furoquinolines 4.
triple bond generates 6. Protodemetallation of the latter af-
fords the enol ether 7 and releases the catalytic species.[11]
Once enol ether 7 is formed, it enters the second catalytic
cycle. Thus, the coordination of the nitrogen atom of the
imine 2 to the platinum catalyst forms 8 and favors the addi-
tion of the enol ether 7 to give the intermediate 9 through a
Mannich-type process.[12] Further reaction of the basic nitro-
gen atom with one of the acidic protons in the a-position to
the oxonium group leads to the amine derivative 10. An
elimination of aniline in 10 gives the diene intermediate 11
which reacts with the previously formed imine complex 8
through a typical Povarov process to furnish the intermedi-
ate 12.[13] Intramolecular nucleophilic addition of the elec-
tron-rich aromatic ring to the oxonium ion, followed by
rearomatization and protodemetallation leads to the final
product 4 closing the second catalytic cycle. To explain the
stereochemistry observed in products 4 we suppose that the
cyclization step in 12 occurs through a chairlike conforma-
tion in which the phenyl group occupies an equatorial posi-
tion (see 12A in Scheme 3; bold bonds were drawn to facili-
tate the visualization of the chairlike conformation).
Formation of the spirofuranquinoline 3a under acidic con-
ditions (see Table 1, entry 2), is easily understood by a
mechanism analogous to that discussed in our previous
work.[7] In a similar way, under neutral conditions, formation
of the spirofuranquinoline 3a could be explained by intra-
molecular nucleophilic addition of the aromatic ring to the
oxonium ion in 9. When an excess of imine 2 is used, and in
particular under the slow addition conditions previously de-
scribed, the concentration of imine 2 in the reaction media
is high and we suppose that the ligand-exchange reaction in
9 to form 8 and the product 10 is favored. Thus, under the
slow addition conditions, the intramolecular protonation in
9 seems to be more favored than the intramolecular nucleo-
philic addition of the aromatic ring to the oxonium ion.
In summary, we have developed a new platinum-catalyzed
Acknowledgements
We gratefully acknowledge financial support from the MEC (CTQ2007-
61048/BQU and predoctoral grant to A.M.). We also thank Dr Angel L.
Suꢁrez for his help in the X-ray structure determination.
Keywords: cyclization · domino reactions · homogeneous
catalysis · platinum · quinolines
[1] See, for example: a) K. Schiemann, S. Anzali, H. Drosdat, U. Emde,
D. Finsinger, J. Gleitz, B. Hock, H. Reubold, F. Zenke (Merck
Patent GMBH, PCT Int. Appl.), WO 2005063735, 2005; [Chem.
Abstr. 2005, 143, 133291]; b) M. Nyerges, Heterocycles 2004, 63,
1685; c) K. Hanada, K. Furuya, K. Inoguchi, M. Miyakawa, N.
Nagata (Kaken Pharma Co Ltd, PCT Int. Appl.), WO 01027086,
2001,; [Chem. Abstr. 2001, 134, 295752]; d) M. Anzini, A. Cappelli,
S. Vomero, G. Giorgi, T. Langer, M. Hamon, N. Merahi, B. M.
Emerit, A. Cagnotto, M. Skorupska, T. Mennini, J. C. Pinto, J. Med.
Chem. 1995, 38, 2692; e) D. Paris, M. Cottin, P. Demonchaux, G.
Augert, P. Dupassieux, P. Lenoir, M. J. Peck, D. Jasserand, J. Med.
Chem. 1995, 38, 669; f) R. W. Carling, P. D. Leeson, A. M. Moseley,
J. D. Smith, K. Saywell, M. D. Trickelbank, J. A. Kemp, G. R. Mar-
shall, A. C. Foster, S. Grimwood, Bioorg. Med. Chem. Lett. 1993, 3,
65; g) A. Nakagawa, Y. Iwai, H. Hashimoto, N. Miyazaki, R. Oiwa,
Y. Takahashi, A. Hirano, N. Shibukawa, Y. Kojima, S. Omura, J. An-
tibiot. 1981, 34, 1408.
[2] a) J. P. Michael, Nat. Prod. Rep. 2005, 22, 627; b) J. P. Michael, Nat.
Prod. Rep. 2004, 21, 650; c) J. P. Michael, Nat. Prod. Rep. 2003, 20,
476; d) J. P. Michael, Nat. Prod. Rep. 2002, 19, 742; e) M. F. Grun-
don in The Alkaloids, Vol. 32 (Ed.: A. Brossi), Academic Press, New
York, 1988, p. 341.
[3] See, for example: a) M. Z. Hoemann, R. L. Xie, R. F. Rossi, S.
Meyer, A. Sidhu, G. D. Cuny, J. R. Hauske, Bioorg. Med. Chem.
Lett. 2002, 12, 129; b) A. Chilin, C. Marzano, A. Guiotto, F. Bacci-
chetti, F. Carlassare, F. Bordin, J. Med. Chem. 2002, 45, 1146;
c) L. K. Basco, S. Mitaku, A.-L. Skaltsounis, N. Ravelomanantsoa, F.
Tillequin, M. Koch, J. Le Bras, Antimicrob. Agents Chemother. 1994,
38, 1169, and references therein. See also references [1d] and [2].
[4] For leading recent references, see: a) Z. Zhang, Q. Zhang, S. Sun, T.
Xiong, Q. Liu, Angew. Chem. 2007, 119, 1756; Angew. Chem. Int.
Ed. 2007, 46, 1726; b) T. Godet, C. Vaxelaire, C. Michel, A. Milet, P.
Belmont, Chem. Eur. J. 2007, 13, 5632; c) A. Fayol J. Zhu, Angew.
reaction for the diasteresoselective construction of furoACTHNUTRGNEU[GN 3,2-
10894
www.chemeurj.org
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 10892 – 10895

Synthesis of Furoquinolines
COMMUNICATION
Chem. 2002, 114, 3785; Angew. Chem. Int. Ed. 2002, 41, 3633. See
also reference [5].
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif
[5] For selected examples, see: a) S. Vellaisamy, C. AvendaÇo, J. C. Me-
nꢃndez, Synlett 2007, 1079–1082; b) Z. Zhou, F. Xu, X. Han, J.
Zhou, Q. Shen, Eur. J. Org. Chem. 2007, 5265; c) K. Nagaiah, D.
Sreenu, R. S. Rao, G. Vashishta, J. S. Yadav, Tetrahedron Lett. 2006,
47, 4409; d) R. Sridhar, P. T. Perumal, Can. J. Chem. 2006, 84, 464;
e) T. Akiyama, H. Morita, K. Fuchibe, J. Am. Chem. Soc. 2006, 128,
13070; f) K. V. N. S. Srinivas, B. Das, Synlett 2004, 1715; g) R. S.
Kumar, R. Nagarajan, S. Chitra, P. T. Perumal, Tetrahedron 2001, 57,
3419; h) G. Sundararajan, N. Prabagaran, B. Varghese, Org. Lett.
2001, 3, 1973; i) B. Crousse, J. P. Bꢃguꢃ, D. Bonnet-Delpon, J. Org.
Chem. 2000, 65, 5009; j) S. Kobayashi, S. Nagayama, J. Am. Chem.
Soc. 1996, 118, 8977.
[10] Neither the platinum complex nor the silver salt are appropriate cat-
alysts in this reaction and the mixture of both is required.
[11] Recent hydroalkoxylation reactions catalyzed by platinum com-
plexes: a) J. Barluenga, A. Fernꢁndez, A. Satrfflstegui, A. Diꢃguez,
F. Rodrꢀguez, F. J. FaÇanꢁs, Chem. Eur. J. 2008, 14, 4153–4156; b) A.
Diꢃguez-Vꢁzquez, C. C. Tzschucke, W. Y. Lam, S. V. Ley, Angew.
Chem. 2008, 120, 216–219; Angew. Chem. Int. Ed. 2008, 47, 209–
212; c) I. Nakamura, C. S. Chan, T. Araki, M. Terada, Y. Yamamoto,
Org. Lett. 2008, 10, 309–312; d) J. Barluenga, A. Diꢃguez, A.
Fernꢁndez, F. Rodrꢀguez, F. J. FaÇanꢁs, Angew. Chem. 2006, 118,
2145–2147; Angew. Chem. Int. Ed. 2006, 45, 2091–2093; e) B. Liu,
J. K. De Brabander, Org. Lett. 2006, 8, 4907–4910; f) H. Qian, X.
Han, R. A. Widenhoefer, J. Am. Chem. Soc. 2004, 126, 9536–9537;
g) D. W. Lucey, J. D. Atwood, Organometallics 2002, 21, 2481–2490.
[12] For an excellent account on s- and p-electrophilic Lewis acids, see:
Y. Yamamoto, J. Org. Chem. 2007, 72, 7817–7831.
[13] Formation of approximately one equivalent of the corresponding
aniline derivative is observed in all these reactions. The role of
dienes 11 as intermediates of the reaction is supported by the isola-
tion, in some particular cases, of dienes analogous to 11 in reactions
performed under the standard conditions. Moreover, diene 11 was
synthesized by an independent method and subjected to the reaction
conditions to give compound 4j in 90% yield.
[6] L. S. Povarov, Russ. Chem. Rev. 1967, 36, 656.
[7] J. Barluenga, A. Mendoza, F. Rodrꢀguez, F. J. FaÇanꢁs, Angew.
Chem. 2008, 120, 7152; Angew. Chem. Int. Ed. 2008, 47, 7044.
[8] For some recent reviews on different uses of platinum catalysts, see:
a) A. R. Chianese, S. J. Lee, M. R. Gagnꢃ, Angew. Chem. 2007, 119,
4118–4136; Angew. Chem. Int. Ed. 2007, 46, 4042–4059; b) A.
Fꢄrstner, P. W. Davies, Angew. Chem. 2007, 119, 3478–3519; Angew.
Chem. Int. Ed. 2007, 46, 3410–3449; c) C. Liu, F. Bender, X. Han,
R. A. Widenhoefer, Chem. Commun. 2007, 3607–3618; d) L. Zhang,
J. Sun, S. A. Kozmin, Adv. Synth. Catal. 2006, 348, 2271–2296; e) L.
AÇorbe, G. Domꢀnguez, J. Pꢃrez-Castells, Chem. Eur. J. 2004, 10,
4938–4943; f) A. M. Echavarren, C. Nevado, Chem. Soc. Rev. 2004,
33, 431–436.
[9] CCDC-689851 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Received: October 16, 2008
Published online: November 12, 2008
Chem. Eur. J. 2008, 14, 10892 – 10895
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10895