Exploiting the divergent reactivity of isocyanoacetates: One-pot three-component synthesis of functionalized angular furoquinolines

Article abstract of DOI:10.1002/ejoc.201101567

A one-pot, three-component synthesis of polysubstituted furo[2,3-c]quinoline 1 was developed based on the new reactivity profile of α-(4-nitrophenyl)-α-isocyanoacetates. Simply mixing aldehydes 2, ortho-alkynylanilines 3, and α-(4-nitrophenyl)-α-isocyanoa

Full text of DOI:10.1002/ejoc.201101567

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101567
Exploiting the Divergent Reactivity of Isocyanoacetates: One-Pot Three-
Component Synthesis of Functionalized Angular Furoquinolines
Marinus J. Bouma,[a] Géraldine Masson,*[a] and Jieping Zhu*[b]
Keywords: Fused-ring systems / Nitrogen heterocycles / Multicomponent reactions / Cycloaddition
A one-pot, three-component synthesis of polysubstituted
furo[2,3-c]quinoline 1 was developed based on the new reac-
tivity profile of α-(4-nitrophenyl)-α-isocyanoacetates. Simply
mixing aldehydes 2, ortho-alkynylanilines 3, and α-(4-nitro-
phenyl)-α-isocyanoacetates 4 in methanol at room tempera-
ture, followed by addition of toluene and heating to reflux,
provided the polysubstituted furo[2,3-c]quinolines in moder-
ate to excellent yields. Mechanistically, the three-component
reaction of 2, 3, and 4 leading to 5-alkoxyoxazoles was fol-
lowed by a domino sequence involving Diels–Alder/retro-
Diels–Alder/oxidation reactions. In this one-pot process, five
chemical bonds were created with concurrent formation of
two heterocyclic rings. The reaction was performed under
thermal conditions and no external reagent was needed to
promote this mechanistically intriguing reaction.
nent synthesis of 2-alkoxyfuro[2,3-c]quinolines 1 by using
α-(4-nitrophenyl)-α-isocyanoacetates as a key reaction part-
ner (Scheme 1).
Introduction
Quinolines and hetero-fused quinolines are ubiquitous
structural motifs found in a large number of biologically
important alkaloids, and they are considered privileged
scaffolds in medicinal chemistry. Furoquinolines are one of
the most important members of this class of heterocy-
cles.[1,2] They are constituents of the Rutaceae and Solana-
ceae plant species[3] and possess a wide range of biological
properties including antimicrobial, antitumor, antiemetic,
antineoplastic, and antimalarial activities.[2a,4] Therefore,
they are important targets for organic synthesis and much
effort has been directed towards the development of the ef-
ficient construction of furoquinolines. Most of the classical
synthetic approaches use a stepwise “ring-by-ring” process
that is often low yielding and do not allow the introduction
of molecular diversity.[3,5,6] While more efficient synthetic
routes have recently been developed for linear furoquinol-
ines,[7] progress still remains to be made in the synthesis of
angular furoquinolines.[8] A few years ago, we disclosed a
one-pot synthesis of 2-N,N-dialkylaminofuro[2,3-c]-
quinolines through a multicomponent domino reaction[9,10]
of ortho-alkynylanilines, α-isocyanoacetamides, and alde-
hydes.[11] Herein, we report a highly efficient multicompo-
Scheme 1. Synthesis of 2-alkoxyfuro[2,3-c]quinolones 1.
On the basis of the substrate design approach,[12] we have
been able to fine-tune the reactivity of α-isocyanoacetates
by simply introducing an additional electron-withdrawing
group in its α-position. We demonstrated that α-(p-ni-
trophenyl)-α-isocyanoacetates[13] display a reactivity profile
similar to that of α-isocyanoacetamides,[11,14,15] rather than
that of the parent α-isocyanoacetates, which is dominated
by the nucleophilicity of the α-carbanion.[16] We have sub-
sequently developed multicomponent syntheses of 5-alkoxy-
oxazoles, furopyrrolones, and pyrrolopyridinones by taking
advantage of the peculiar reactivity of this type of α-isocy-
anoacetate.[13]
Taking advantage of the potential chemical reactivity of
5-alkoxyoxazoles, a three-component synthesis of 2-alkyl-
oxyfuroquinolines 1 from aldehydes 2, ortho-alkynylanilines
3, and α-isocyanoacetates 4 was envisaged according to the
sequence shown in Scheme 2. Thus, condensation of alde-
hydes 2 and amines 3 should give imines 5, which would
react with the divalent isocyanide carbon atom of α-isocy-
anoacetates 4 to produce 5-alkoxyoxazoles 7. Intramolecu-
lar Diels–Alder cycloaddition[17] of 7 between the oxazole
and the tethered triple bond would furnish oxa-bridged het-
erocycles 8, which could undergo fragmentation by a retro-
[a] Centre de Recherche de Gif,
Institut de Chimie des Substances Naturelles, CNRS,
91198 Gif-sur-Yvette Cedex, France
Fax: +33-1-69077247
E-mail: masson@icsn.cnrs-gif.fr
[b] Institute of Chemical Sciences and Engineering,
Ecole Polytechnique Fédérale de Lausanne (EPFL),
EPFL-SB-ISIC-LSPN,
1015 Lausanne, Switzerland
Fax: +41-21-6939740
E-mail: jieping.zhu@epfl.ch
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101567.
Eur. J. Org. Chem. 2012, 475–479
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
475

M. J. Bouma, G. Masson, J. Zhu
SHORT COMMUNICATION
Diels–Alder process to furnish 10 and benzonitrile deriva- quinoline 1a in 89% yield (Scheme 3). 4-Nitrophenylcy-
tives 9. A subsequent oxidation mediated by atmospheric anide (9a), formed during the retro-Diels–Alder step, was
oxygen could occur to give aromatic 2-alkoxyfuro[2,3-c]- also isolated from the reaction mixture. It is interesting to
quinolines 1. In this complex domino transformation, we note that at least six distinct elementary reactions, including
assumed that the two irreversible steps, formation of the condensation of an aldehyde with an amine, nucleophilic
oxazole and the retro-Diels–Alder reaction, would provide addition of an isocyanide to an imine, oxazole formation,
the driving forces to guarantee the success of the overall intramolecular Diels–Alder cycloaddition of the oxazole,
multicomponent domino process.
retro-Diels–Alder, and oxidation, occurred in an ordered
manner to provide α-alkoxyfuro[2,3-c]quinolines 1. It is
worth to note that two rings were created with concurrent
formation of five chemical bonds. The efficiency of this
three-component reaction (89% yield) is therefore remarka-
bly high if one counts the yield per chemical bond forma-
tion.
Scheme 3. Survey of reaction conditions for the three-component
domino synthesis of α-alkoxyfuro[2,3-c]quinoline 1a.
The scope of this novel domino multicomponent reaction
was next examined by varying the structure of the amines
and aldehydes (Figure 1). Because the 4-nitrophenyl substit-
uent of isocyanide 4a is not incorporated into the structure
of the final product, the invariableness of this input is not
a major concern in this reaction. By applying the standard
conditions (MeOH, r.t.; then toluene, reflux), the furoquin-
olines were isolated in moderate to excellent yields from
both aliphatic and aromatic aldehydes having different elec-
tronic and steric properties (Figure 2). When aniline deriva-
tives 3c (R = NO2) and 3d (R = COMe)[20] bearing electron-
poor acetylene units were subjected to the same conditions,
the reaction slowed down significantly. Fortunately, desired
2-alkoxyfuroquinolines 1h and 1i (Figure 2) were isolated in
Scheme 2. Three-component domino process to furoquinolines, a
mechanistic working hypothesis.
Results and Discussion
To validate our hypothesis, cyclohexanecarbaldehyde
(2a), methyl 3-(2-aminophenyl)propiolate (3a) and ethyl α-
(p-nitrophenyl)-α-isocyanoacetate (4a) were selected as test
substrates to survey the reaction conditions. When the reac-
tion was carried out in toluene (c = 0.1 m) at room tempera-
ture or at reflux, neither 2-alkoxyfuro[2,3-c]quinoline 1a
nor 5-alkyloxyoxazole 7 was formed (Scheme 2). Addition
of promoters (1.0 equiv.) such as NH4Cl, I2, LiBr, ZnCl2,
Et3N, pTSA, or camphorsulfonic acid failed to trigger the
reaction efficiently. The undesired ring–chain tautomeri-
zation of isocyanoacetate 4a leading to the 2-unsubstituted
oxazole was instead observed under these conditions.[18] In
polar solvents, such as methanol, only a trace amount of
oxazole was detected.[19] However, increasing the concentra-
tion of the reaction mixture had a dramatic effect, and
when the reaction was performed in methanol at 1.0 m, the
three-component reaction went to completion at room tem-
perature leading to oxazole 7 after 22 h. Performing the re-
action at higher temperature under otherwise identical con-
ditions did not give the desired Diels–Alder product. Fortu-
nately, addition of toluene to the reaction mixture followed
by heating to reflux for 5 h afforded 2-alkoxyfuro[2,3-c]- Figure 1. Structures of amines and aldehydes.
476 Eur. J. Org. Chem. 2012, 475–479
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Synthesis of Functionalized Angular Furoquinolines
excellent yields when the reaction was performed in re-
fluxing xylene instead of toluene. Gratefully, aniline 3b (R
= H) bearing an electronically neutral acetylene unit and
aniline 3e bearing a terminal acetylene unit participated in
the reaction efficiently to afford the corresponding adducts
1k and 1j in 78 and 58% yield, respectively.
Experimental Section
Representative Procedure for the Three-Component Synthesis of α-
Alkoxyfuro[2,3-c]quinolones 1: Aldehyde 2a (1.0 mmol) and amine
3a (1.0 mmol) were dissolved in methanol (1.0 mL) and stirred for
30 min. α-Isocyanoacetate 4a (1.0 equiv.) was added and stirring
was continued at room temperature until the disappearance of the
α-isocyanoacetate. Toluene (1 mL) was added, and the reaction was
heated at reflux for 5 h. The crude product was purified by flash
column chromatography on silica gel (heptanes/EtOAc, 3:1) to give
desired furoquinoline 1a (89%) as a white solid. M.p. 96–97 °C.
IR: ν = 2933, 2850, 1702, 1575, 1452, 1359, 1256, 1086, 1013, 872,
˜
760 cm–1. 1H NMR (500 MHz, CDCl3): δ = 9.26 (dd, J = 8.4,
1.2 Hz, 1 H), 8.12 (dd, J = 8.4, 1.2 Hz, 1 H), 7.66 (ddd, J = 8.4,
6.9, 1.2 Hz, 1 H), 7.55 (ddd, J = 8.4, 6.9, 1.2 Hz, 1 H), 4.74 (q, J
= 7.1 Hz, 2 H), 3.99 (s, 3 H), 3.27 (m, 1 H), 1.80–2.09 (m, 7 H),
1.63 (t, J = 7.1 Hz, 3 H), 1.38–1.60 (m, 3 H) ppm. 13C NMR
(75 MHz, CDCl3, 293 K): δ = 164.8 (Cq), 163.9 (Cq), 151.1 (Cq),
145.5 (Cq), 139.5 (Cq), 129.2 (CH), 129.0 (Cq), 127.7 (CH), 126.5
(CH), 125.3 (CH), 122.3 (Cq), 90.0 (Cq), 68.4 (CH2), 51.5 (CH3),
42.9 (CH), 31.0 (CH2), 26.5 (CH2), 26.1 (CH2), 14.9 (CH3) ppm.
HRMS (ESI): calcd. for C21H24NO4 [M + H]+ 354.1705; found
354.1707.
Supporting Information (see footnote on the first page of this arti-
cle): Full characterization data and copies of the 1H and 13C NMR
spectra.
Acknowledgments
Financial support from the Centre National de la Recherche
Scientifique (CNRS) is gratefully acknowledged. M. B. thanks the
Institut de Chimie des Substances Naturelles (ICSN) for a doctoral
fellowship.
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Conclusions
In summary, we described a three-component synthesis
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mechanistically complex reaction that led to the creation of
five chemical bonds and two heterocyclic rings. The opera-
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Eur. J. Org. Chem. 2012, 475–479
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M. J. Bouma, G. Masson, J. Zhu
SHORT COMMUNICATION
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Received: October 27, 2011
Published Online: December 5, 2011
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