A general protocol for the solvent- and catalyst-free synthesis of 2-styrylquinolines under focused microwave irradiation

Article abstract of DOI:10.1055/s-0030-1260330

Focused microwave irradiation promoted the very efficient synthesis of 2-styrylquinolines by reaction between quinaldines and benzaldehydes or cinnamaldehydes in the presence of acetic anhydride. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260330

LETTER
2577
A General Protocol for the Solvent- and Catalyst-Free Synthesis of
2-Styrylquinolines under Focused Microwave Irradiation
S
ynthesis of 2-Styrylqu
a
inolines un
t
der Fo
t
cused M
e
icrowave
o
Irradiation Staderini,a Nieves Cabezas,a Maria Laura Bolognesi,b J. Carlos Menéndez*a
a
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Fax +34(91)3941822; E-mail: josecm@farm.ucm.es
b
Dipartimento di Scienze Farmaceutiche, Universitá di Bologna, via Belmeloro 6, 40126 Bologna, Italy
Received 10 June 2011
The most common method for the synthesis of styrylquin-
olines is based on acid- or base-catalyzed condensation of
2-methylquinolines (quinaldines) with suitable aromatic
aldehydes.5a–d,8 However, this aldol-type condensation re-
quires high temperatures and gives only moderate yields
in many cases. An attempt has been made to apply micro-
wave irradiation to improve this reaction, but the condi-
tions described involve the use of a domestic oven, which
leads to well-known safety concerns and serious repro-
ducibility issues related to the generation of an uneven
pattern of hot and cold spots inside the oven cavity.9 Even
more importantly, the method was not general, allowing
only the preparation of carboxyquinolines and little struc-
tural variation on the styryl chain.10 A conceptually differ-
ent access to styrylquinolines has recently been
developed, based on the preparation of 2-styryl-1,2,3,4-
tetrahydroquinolines via a vinylogous Povarov reaction
followed by their aromatization in the presence of palladi-
um, but unfortunately it lacks generality in terms of the
substitution on the styryl side chain.8 Hence, the general-
ization and optimization of the classical aldol-based pro-
tocol is still an important goal.
Abstract: Focused microwave irradiation promoted the very effi-
cient synthesis of 2-styrylquinolines by reaction between quinaldi-
nes and benzaldehydes or cinnamaldehydes in the presence of acetic
anhydride.
Key words: aldol condensations, heterocycles, quinolines, micro-
wave-assisted synthesis
The quinoline ring system1 is present as an essential struc-
tural fragment in a large number of natural and unnatural
compounds exhibiting a broad variety of applications in
materials science and pharmacology. Indeed, thanks to
their presence in a broad variety of drugs, quinolines rep-
resent a paradigm of privileged structures.2
Among quinoline derivatives, there is much current inter-
est in 2-styrylquinolines, due primarily to the fact that
these compounds, exemplified by FZ41 and KHD161,
provide a novel and promising strategy for AIDS
therapy3,4 because of their ability to act as HIV integrase
inhibitors5 by a previously unknown mechanism.6
Styrylquinolines (e.g., compound 1) have also been iden-
tified as useful imaging agents for b-amyloid plaques on
Alzheimer’s disease human brain sections (Figure 1).7
In this context, we describe here our findings on the use of
focused microwave irradiation to overcome these limita-
tions, leading to a general synthesis of 2-styrylquinolines.
As shown in Scheme 1, microwave irradiation of solvent-
free mixtures of quinaldine derivatives 2, aromatic alde-
hydes, and acetic anhydride afforded excellent yields of
styrylquinolines 3 in a single synthetic operation. This
transformation must proceed through a domino sequence
comprising an initial aldol addition, followed by O-acety-
lation and elimination.
R2
HO2C
N
OH
OH
OR1
FZ41 R1 = CH3; R2 = OH
KHD161 R1 = H; R2 = H
MeO
R1
CHO
Ac2O
+
+
N
Ar
n
R2
N
Me
2
1
MW, 200 W,
130–180 °C, 1 h
Figure 1 Some pharmacologically relevant 2-styrylquinoline deri-
vatives
R1
R2
N
n Ar
3
n = 0, 1
SYNLETT 2011, No. 17, pp 2577–2579
Advanced online publication: 29.09.2011
x
x
.x
x
.2
0
1
1
Scheme 1 Microwave-assisted synthesis 2-styrylquinolines
DOI: 10.1055/s-0030-1260330; Art ID: D18111ST
© Georg Thieme Verlag Stuttgart · New York

2578
M. Staderini et al.
LETTER
In conclusion, we have developed a practical, user-friend-
ly, and general microwave-assisted protocol allowing the
solvent-free transformation of quinaldines into
styrylquinolines. This reaction generates a carbon–carbon
double bond in a very efficient, diastereoselective fashion,
with water and acetic acid as the only side products.
N
N
Cl
3a (150 °C, 63%)
3b (150 °C, 77%)
N
N
N
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
OMe
3c (180 °C, 70%)
3d (130 °C, 65%)
Me
Cl
Acknowledgment
OMe
N
N
We thank MICINN (grant CTQ2009-12320-BQU) and UCM
(Grupos de Investigación Consolidados, grant GR35/10-A-920234)
for financial support.
OMe
MeO
3e (180 °C, 93%)
3f (180 °C, 90%)
Cl
References and Notes
N
N
(1) For reviews of quinoline-related compounds, see:
(a) Michael, J. P. Nat. Prod. Rep. 2008, 25, 166.
F
F
3g (150 °C, 95%)
3h (150 °C, 86%)
(b) Michael, J. P. Nat. Prod. Rep. 2007, 24, 223.
(c) Kouznetsov, V. V.; Vargas Méndez, L. Y.;
Meléndez Gomez, C. M. Curr. Org. Chem. 2005, 9, 141.
Cl
N
(d) Michael, J. P. Nat. Prod. Rep. 2004, 21, 650.
(e) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627.
MeO
N
OMe
3j (180 °C, 84%)
(2) Bongarzone, S.; Bolognesi, M. L. Curr. Opin. Drug
Discovery Dev. 2011, 6, 251.
3i (150 °C, 78%)
(3) For reviews of the potential of integrase inhibitors as anti-
HIV agents, see: (a) Makhija, M. T. Curr. Med. Chem. 2006,
13, 2429. (b) Pommier, Y.; Johnson, A. A.; Marchand, C.
Nat. Rev. Drug Discovery 2005, 4, 236. (c) Andréola, M.
L.; De Soultrait, V. R.; Fournier, M.; Parissi, V.; Desjobert,
C.; Litvak, S. Expert Opin. Ther. Targets 2002, 6, 433.
(d) d’Angelo, J.; Mouscadet, J.-F.; Desmaële, D.; Zouhiri,
F.; Leh, H. Pathol. Biol. 2001, 49, 237.
Me
N
Me
N
N
3l (130 °C, 87%)
OMe
3k (180 °C, 77%)
Cl
(4) Raltegravir, an integrase inhibitor, has recently reached the
market as an anti-AIDS agent. For a study of its clinical
efficacy, see: Steigbigel, R. T.; Cooper, D. A.; Kumar, P. N.;
Eron, J. E.; Schechter, M.; Markowitz, M.; Loutfy, M. R.;
Lennox, J. L.; Gatell, J. M.; Rockstroh, J. K.; Katlama, C.;
Yeni, P.; Lazzarin, A.; Clotet, B.; Zhao, J.; Chen, J.; Ryan,
D. M.; Rhodes, R. R.; Killar, J. A.; Gilde, L. R.; Strohmaier,
K. M.; Meibohm, A. R.; Miller, M. D.; Hazuda, D. J.;
Nessly, M. L.; DiNubile, M. J.; Isaacs, R. D.; Nguyen, B.-Y.;
Teppler, H. N. Engl. J. Med. 2008, 359, 339.
N
3m (150 °C, 93%)
Me
N
Cl
3n (150 °C, 74%)
Figure 2 Scope and yields of the 2-styrylquinoline synthesis
(5) (a) Normand-Bayle, M.; Bénard, C.; Zouhiri, F.; Mouscadet,
J.-F.; Leh, H.; Thomas, C.-M.; Mbemba, G.; Desmaële, D.;
d’Angelo, J. Bioorg. Med. Chem. Lett. 2005, 15, 4019.
(b) Bénard, C.; Zouhiri, F.; Normand-Bayle, M.; Canet, M.;
Desmaële, D.; Leh, H.; Mouscadet, J.-F.; Mbemba, G.;
Thomas, C.-M.; Bonnenfant, S.; Le Bret, M.; d’Angelo, J.
Bioorg. Med. Chem. 2004, 14, 2473. (c) Mousnier, A.; Leh,
H.; Mouscadet, J.-F.; Dargemont, C. Mol. Pharmacol. 2004,
66, 783. (d) Polanski, J.; Zouhiri, F.; Jeanson, L.; Desmaële,
D.; d’Angelo, J.; Mouscadet, J.-F.; Gieleciak, R.; Gasteiger,
J.; Le Bret, M. J. Med. Chem. 2002, 45, 4647. (e) Yuan, H.;
Parrill, A. L. Bioorg. Med. Chem. 2002, 10, 4169.
The yields and scope of the reaction are summarized in
Figure 2, the analysis of which leads to the following con-
clusions: (a) The method is general in terms of the nature
of the substituent in the aromatic ring of the styryl chain,
which can be either electron-releasing or electron-with-
drawing with little effect on the yield (cf. compounds 3a–
c). This side chain may also contain a pyridine ring in-
stead of benzene (compound 3d). (b) The quinoline ring
may also contain either electron-withdrawing substituents
at C-6 (cf. compounds 3e–h) or C-7 (cf. compounds 3i–l).
(c) By employing cinnamaldehyde derivatives as starting
materials,11 the method can also be applied to the prepara-
tion of compounds with extended conjugation such as 3m
and 3n. Yields were normally excellent, and the experi-
mental protocol was simple and user-friendly.12
(f) Oulali, M.; Labulais, C.; Leh, H.; Gill, D.; Desmaële, D.;
Mekouar, K.; Zouhiri, F.; d’Angelo, J.; Auclair, C.;
Mouscadet, J.-F.; Le Bret, M. J. Med. Chem. 2002, 43,
1949. (g) d’Angelo, J.; Mouscadet, J.-F.; Desmaele, D.;
Zouhiri, F.; Leh, H. Pathol. Biol. 2001, 49, 237.
(h) Zouhiri, F.; Mouscadet, J.-F.; Mekouar, K.; Desmaële,
D.; Savouré, D.; Leh, H.; Subra, F.; Le Bret, M.; Auclair, C.;
Synlett 2011, No. 17, 2577–2579 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Styrylquinolines under Focused Microwave Irradiation
2579
d’Angelo, J. J. Med. Chem. 2000, 43, 1533. (i) Ouali, M.;
representative compounds are given below. For further
characterization data, see the Supporting Information.
(E)-2-(4-Fluorostyryl)-6-methoxyquinoline (3h)
Pale yellow solid; mp 138–141 °C. IR (neat): nmax = 1592.4,
1509.8, 1231.9, 1164.1, 1030.8, 965.4, 856.2, 837.0 cm–1. 1H
NMR (250 MHz, CDCl3): d = 3.96 (s, 3 H), 7.08–7.14 (m, 3
H), 7.33 (d, J = 16.6 Hz, 1 H), 7.39 (dd, J = 9.3, 2.8 Hz, 1 H),
7.58–7.65 (m, 4 H), 8.02 (d, J = 8.9 Hz, 1 H), 8.05 (d, J = 8.4
Hz, 1 H). 13C NMR (62.9 MHz, CDCl3): d = 56.0 (CH3),
105.6 (CH), 116.2 (d, J = 21.7 Hz, 2 CH), 119.2 (CH), 122.9
(CH), 128.7 (C), 129.1 (d, J = 8.1 Hz, 2 CH), 130.9 (CH),
132.5 (CH), 133.2 (C), 133.3 (C), 135.7 (CH), 144.6 (C),
153.9 (C), 158.1 (C), 163.21 (d, J = 248.4 Hz, C). Anal.
Calcd for C18H14FNO: C, 77.40; H, 5.05; N, 5.01. Found: C,
77.15; H, 5.01; N, 4.77.
Laboulais, C.; Leh, H.; Gill, D.; Desmaele, D.; Mekouar, K.;
Zouhiri, F.; d’Angelo, J.; Auclair, C.; Mouscadet, J.-F.;
Le Bret, M. J. Med. Chem. 2000, 43, 1949. (j) Mekouar, K.;
Mouscadet, J.-F.; Desmaële, D.; Subra, F.; Leh, H.; Savouré,
D.; Auclair, C.; d’Angelo, J. J. Med. Chem. 1998, 41, 2846.
(6) Bonnenfant, S.; Thomas, C. M.; Vita, C.; Subra, C.; Deprez,
E.; Zouhiri, F.; Desmaële, D.; d’Angelo, J.; Mouscadet,
J.-F.; Leh, H. J. Virol. 2004, 78, 5728.
(7) Li, Q.; Min, J.; Ahn, Y.-H.; Namm, J.; Kim, E. M.; Lui, R.;
Kim, H. Y.; Ji, Y.; Wu, H.; Wisniewski, T.; Chang, Y.-T.
ChemBioChem 2007, 8, 1679.
(8) (a) Dabiri, M.; Salehi, P.; Baghbanzadeh, M.; Nikcheh,
M. S. Tetrahedron Lett. 2008, 49, 5366. (b) Leonard, J. T.;
Roy, K. Eur. J. Med. Chem. 2008, 43, 81. (c) Makhija,
M. T. Curr. Med. Chem. 2006, 13, 2429. (d) Bonnenfant,
S.; Thomas, C.-M.; Vita, C.; Subra, C.; Deprez, E.; Zouhiri,
F.; Desmaele, D.; d’Angelo, J.; Mouscadet, J.-F.; Leh, H.
J. Virol. 2004, 78, 5728. (e) Yuan, H. B.; Parrill, A. L.
Bioorg. Med. Chem. 2002, 10, 4169.
(E)-7-Chloro-2-(4-methoxystyryl)quinolone (3j)
White solid; mp 149–151 °C. IR (neat): nmax = 1604.2,
1511.3, 1408.0, 1250.8, 1177.9, 1032.8, 970.1, 831.8 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.89 (s, 3 H), 6.98 (d,
J = 8.7 Hz, 2 H), 7.23 (d, J = 16.1 Hz, 1 H), 7.46 (dd, J = 8.6,
(9) For a discussion, see: Kappe, A. O. Angew. Chem. Int. Ed.
2.1 Hz, 1 H), 7.61–7.75 (m, 5 H), 8.09–8.13 (m, 2 H). 13
C
2004, 43, 6250.
NMR (62.9 MHz, CDCl3): d = 55.8 (CH3), 114.7 (2 CH),
120.0 (CH), 125.9 (C), 126.7 (CH), 127.3 (CH), 128.5 (CH),
129.1 (CH), 129.2 (2 CH), 129.5 (C), 135.2 (CH), 135.9 (C),
136.4 (CH), 149.1 (C), 157.7 (C), 160.7 (C). Anal. Calcd for
C18H14ClNO: C, 73.10; H, 4.77; N, 4.74. Found: C, 73.19; H,
4.81; N, 4.86.
(10) Musiol, R.; Podeszwa, B.; Finster, J.; Niedbala, H.; Polansli,
J. Monatsh. Chem. 2006, 137, 1211.
(11) For the preparation of these starting materials, see:
(a) Sridharan, V.; Avendaño, C.; Menéndez, J. C.
Tetrahedron 2007, 63, 673. (b) Fedoryak, O. D.; Dore, T.
M. Org. Lett. 2002, 4, 3419. (c) Chen, X.-Y.; Shi, J.; Li,
Y.-M.; Wang, F.-L.; Wu, X.; Guo, Q.-X.; Liu, L. Org. Lett.
2009, 11, 4426.
6-Chloro-2-[(1E,3E)-4-phenylbuta-1,3-dienyl]quinoline
(3m)
Yellow solid; mp 105–108 °C. IR (neat): nmax = 1590.2,
1485.5, 1070.0, 1001.7, 892.3, 825.7, 751.7 cm–1. 1H NMR
(250 MHz, CDCl3): d = 6.87–7.15 (m, 3 H), 7.31–7.43 (m, 3
H), 7.52–7.62 (m, 4 H), 7.65 (dd, J = 9.0, 2.3 Hz, 1 H) 7.78
(d, J = 2.3 Hz, 1 H), 8.01 (d, J = 8.9 Hz, 1 H), 8.04 (d, J = 8.5
Hz, 1 H). 13C NMR (62.9 MHz, CDCl3): d = 120.8 (CH),
126.6 (CH), 127.2 (2 CH), 128.2 (C), 128.7 (CH), 128.8
(CH), 129.2 (2 CH), 131.0 (CH), 131.2 (CH), 132.1 (CH),
132.7 (CH), 135.7 (CH), 135.8 (CH), 136.8 (CH), 137.3 (C),
147.1 (C), 156.6 (C). Anal. Calcd for C19H14ClN: C, 78.21;
H, 4.84; N, 4.80. Found: C, 78.45; H, 5.01; N, 5.03.
(12) General Experimental Procedure
The suitable quinaldine derivative (1 mmol) and the
corresponding aromatic aldehyde (1 equiv) were suspended
in Ac2O (0.5 mL) in a pressure-tight microwave tube
containing a stirring bar. The reaction mixture was heated
under microwave irradiation for 1 h at 130–180 °C, with an
irradiation power of 200 W, using a CEM Discover SP
microwave reactor. The solvent was removed under reduced
pressure to give a black residue that was purified by chroma-
tography through a silica column using PE–EtOAc (90:10,
v/v) as the mobile phase. Characterization data for three
Synlett 2011, No. 17, 2577–2579 © Thieme Stuttgart · New York

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