A new and efficient one-pot procedure for the synthesis of 2-styrylquinolines

Article abstract of DOI:10.1016/j.tetlet.2008.06.054

A one-pot combination of a modified Friedl?nder annulation and a Knoevenagel condensation provides 2-styrylquinolines in good to excellent yields. A variety of substrates are reacted in one-pot in the presence of 1-methylimidazolium trifluoroacetate ([Hmim]TFA).

Full text of DOI:10.1016/j.tetlet.2008.06.054

Tetrahedron Letters 49 (2008) 5366–5368
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A new and efficient one-pot procedure for the synthesis of 2-styrylquinolines
b,
a
a
Minoo Dabiri a, , Peyman Salehi , Mostafa Baghbanzadeh , Maryam Shakouri Nikcheh
*
*
a Department of Chemistry, Faculty of Science, Shahid Beheshti University, Postal Code 1983963113, Evin, Tehran 19835-389, Iran
b Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, PO Box 19835-389, Evin, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot combination of a modified Friedländer annulation and a Knoevenagel condensation provides 2-
styrylquinolines in good to excellent yields. A variety of substrates are reacted in one-pot in the presence
of 1-methylimidazolium trifluoroacetate ([Hmim]TFA).
Received 28 April 2008
Revised 3 June 2008
Accepted 10 June 2008
Available online 14 June 2008
Ó 2008 Published by Elsevier Ltd.
Keywords:
Heterocycles
Quinoline
Aldehyde
Ionic liquid
Friedländer annulation
R2
R3
N
Quinolines 1 and their derivatives are very important heterocy-
clic compounds because of their wide occurrence in natural prod-
ucts1–3 and biologically active compounds.4–9 A large variety of
quinolines display interesting physiological activities and have
found applications as pharmaceuticals and agrochemicals, as well
as being general synthetic building blocks.2 Among the various
classes of quinolines, 2-styryl-substituted derivatives 2 form an
important component of pharmacologically active compounds,
associated with a wide spectrum of biological activities10–24 such
as HIV integrase inhibition.17–24 In this respect, d’Angelo and co-
workers reported that polyhydroxylated styrylquinolines, exempli-
fied by 3, are micromolar inhibitors of the third essential enzyme
of HIV-1: integrase (IN), blocking replication of the virus in cell
cultures and are themselves devoid of cytotoxicity (Fig. 1).10–16
The general method for the synthesis of these derivatives is via
condensation of 2-methylquinolines with aromatic aldehydes
under basic or acidic conditions.17–24 Thus, 2-methylquinolines
are key intermediates in the synthesis of 2-styrylquinolines.
Friedländer annulation is one of the most simple and straight-
forward approaches for the synthesis of 2-methylquinolines.25
In this study, we have developed a novel and facile method for
the synthesis of 2-styrylquinolines bearing different groups at the
3-position using the Friedländer reaction of a 2-aminoarylketone
and a methylketone followed by Knoevenagel condensation with
an aromatic aldehyde in the presence of 1-methylimidazolium
R2
R1
R1
X
X
N
Ar
1
2
OH
OH
HO2C
N
OH
3
Figure 1.
R2
R2
N
Knoevenagel
condensation
R1
O
H
R1
Ar
X
N
CH3
X
Ar
R2
R1
O
O
CH3
X
NH2
* Corresponding authors. Fax: +98 21 22431663 (M. Dabiri); fax: +98 21
22431783 (P. Salehi).
E-mail addresses: m-dabiri@sbu.ac.ir (M. Dabiri), p-salehi@sbu.ac.ir (P. Salehi).
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.06.054

M. Dabiri et al. / Tetrahedron Letters 49 (2008) 5366–5368
5367
trifluoroacetate ([Hmim]TFA)26 as a Brønsted acidic ionic liquid (IL)
(Scheme 1).
We have reported previously [Hmim]TFA as an efficient acidic
IL for the synthesis of heterocyclic compounds.27,28 Also it was
shown that [Hmim]TFA promoted the Knoevenagel condensation
of CH-acids and aromatic aldehydes.29 Thus, we decided to investi-
gate the one-pot synthesis of 2-styryl-substituted quinolines in
[Hmim]TFA. After extensive optimization, we found that the two
steps could be carried out in a general and efficient one-pot process
to afford a variety of 2-styrylquinolines.30 As outlined in Table 1,
addition of 0.5 equiv of [Hmim]TFA to a reaction mixture contain-
ing a 1:1 ratio of 2-aminoarylketone:methyl ketone at 80 °C for 2 h
was optimal for the formation of 2-methylquinolines. Subsequent
treatment with 1 equiv of aromatic aldehyde, followed by heating
Table 1
Synthesis of 2-styrylquinolines
Ph
O
O
X
R
X
o
1. [Hmim]TFA (0.5 equiv), 2 h, 80 C
Ph
R
+
CH3
(1 equiv)
2. Ar CHO
N
Ar
NH2
Entry
1
X
R
Ar
Product
Yielda (%)
Ph
O
O
OEt
H
COOEt
4-ClC6H4
87
N
Cl
2a
Ph
OEt
O
2
3
4
5
6
7
8
H
COOEt
COOEt
COOEt
COOEt
COOMe
COOMe
COOEt
COOMe
4-HOC6H4
4-MeOC6H4
4-O2NC6H4
4-ClC6H4
3-Pyridyl
4-Pyridyl
4-Pyridyl
C6H5
84
81
84
82
78
80
78
82
N
OH
2b
Ph
Cl
Cl
OEt
OEt
Cl
Cl
Cl
H
N
OMe
2c
Ph
O
O
N
NO
2 2d
Ph
Cl
OEt
N
Cl
2e
Ph
N
O
OMe
N
2f
Ph
O
O
O
Cl
Cl
Cl
OMe
Cl
Cl
Cl
N
N
N
2g
Ph
OEt
N
2h
Ph
OMe
9
N
2i
a
Isolated yield.

5368
M. Dabiri et al. / Tetrahedron Letters 49 (2008) 5366–5368
9. Chen, Y.-L.; Fang, K.-C.; Sheu, J.-Y.; Hsu, S.-L.; Tzeng, C.-C. J. Med. Chem. 2001, 44,
2374–2377.
at 80 °C for 2 h, afforded 2-styryl-substituted quinolines in yields
typically exceeding 78%.
10. Mekouar, K.; Mouscadet, J.-F.; Desmaële, D.; Subra, F.; Leh, H.; Savouré, D.;
Auclair, C.; d’Angelo, J. J. Med. Chem. 1998, 41, 2846–2857.
11. Zouhiri, F.; Mouscadet, J.-F.; Mekouar, K.; Desmaële, D.; Savouré, D.; Leh, H.;
Subra, F.; Le Bret, M.; Auclair, C.; d’Angelo, J. J. Med. Chem. 2000, 43, 1533–1540.
12. Ouali, M.; Laboulais, 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. 2000, 43,
1949–1957.
13. Ouali, M.; Laboulais, C.; Leh, H.; Gill, D.; Xhuvani, E.; Zouhiri, F.; Desmaële, D.;
d’Angelo, J.; Auclair, C.; Mouscadet, J.-F.; Le Bret, M. Acta Biochim. Pol. 2000, 47,
11–22.
14. d’Angelo, J.; Mouscadet, J.-F.; Desmaële, D.; Zouhiri, F.; Leh, H. Pathol. Biol.
2001, 49, 237–246.
15. Burdujan, R.; d’Angelo, J.; Desmaële, D.; Zouhiri, F.; Tauc, P.; Brochon, J.-C.;
Auclair, C.; Mouscadet, J.-F.; Pernot, P.; Tfibel, F.; Enescu, M.; Fontaine-Aupart,
M.-P. Phys. Chem. Chem. Phys. 2001, 3, 3797–3804.
16. Zouhiri, F.; Desmaële, D.; d’Angelo, J.; Ourevitch, M.; Mouscadet, J.-F.; Leh, H.;
Le Bret, M. Tetrahedron Lett. 2001, 42, 8189–8192.
17. Normand-Bayle, M.; Benard, C.; Zouhiri, F.; Mouscadet, J.-F.; Leh, H.; Thomas,
C.-M.; Mbemba, G.; Desmaële, D.; d’Angelo, J. Bioorg. Med. Chem. Lett. 2005, 15,
4019–4022.
18. Benard, 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, 2473–2476.
19. Mousnier, A.; Leh, H.; Mouscadet, J.-F.; Dargemont, C. Mol. Pharmacol. 2004, 66,
783.
Aromatic aldehydes carrying different functional groups reacted
satisfactorily under the reaction conditions as can be seen in Table
1. Heteroaromatic aldehydes were equally amenable to these con-
ditions with pyridine-3-carbaldehyde providing the corresponding
2-styrylquinoline in 78% yield. Prominent among the advantages of
this new method are operational simplicity, good yields, short
reaction times, and an easy work-up procedure without using
any chromatographic methods. It is worthy to note that in previous
reports, condensation of 2-methylquinolines and aromatic alde-
hydes is performed under harsh reaction conditions and requires
long reaction times.
In conclusion, a new one-pot procedure for the synthesis of 2-
styrylquinolines is described that utilizes a Friedländer reaction
promoted by [Hmim]TFA, followed by a clean and rapid [Hmim]T-
FA-mediated Knoevenagel condensation to afford the correspond-
ing styrylquinoline. To the best of our knowledge, this is the first
report on the synthesis of styrylquinolines starting from commer-
cially available 2-aminoarylketones and methyl ketones. [Hmim]T-
FA tolerated a range of aldehydes. In addition, this methodology is
cost effective and amenable to large scale synthesis.
20. 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–
5736.
21. 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, 4647–4654.
22. Yuan, H. B.; Parrill, A. L. Bioorg. Med. Chem. 2002, 10, 4169–4183.
23. Makhija, M. T. Curr. Med. Chem. 2006, 13, 2429–2441.
24. Pommier, Y.; Johnson, A. A.; Marchand, C. Nat. Rev. Drug Discovery 2005, 4,
236–248.
Acknowledgment
The authors would like to acknowledge financial support from
the Research Council of Shahid Beheshti University.
25. Cheng, C. C.; Yan, S. J. Org. React. 1982, 28, 37.
26. Zhao, G.; Jiang, T.; Gao, H.; Han, B.; Huang, J.; Sun, D. Green Chem. 2004, 6, 75–
77.
Supplementary data
27. Dabiri, M.; Salehi, P.; Baghbanzadeh, M.; Shakouri, M.; Otokesh, S.; Ekrami, T.;
Doosti, R. J. Iran. Chem. Soc. 2007, 4, 393–401.
28. Dabiri, M.; Baghbanzadeh, M.; Arzroomchilar, E. Catal. Commun. 2008, 9, 939–
942.
29. Darvatkar, N. B.; Deorukhkar, A. R.; Bhilare, S. V.; Salunkhe, M. M. Synth.
Commun. 2006, 36, 3042–3051.
Experimental procedures and characterization data for com-
pounds 2a–i are available. Supplementary data associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2008.06.054.
30. Typical procedure for the synthesis of 2-styrylquinolines: To a mixture of 2-
amino-5-chlorobenzophenone (0.231 g, 1 mmol, 1.0 equiv), and methyl
acetoacetate (0.116 g, 1 mmol, 1 equiv) was added 0.1 g (0.5 mmol, 0.5 equiv)
of [Hmim]TFA, and the reaction mixture was heated at 80 °C. After 2 h,
benzaldehyde was added and the reaction mixture was stirred for 2 h at 80 °C.
After completion of the reaction, which was indicated by TLC (eluent: n-
hexane/ethyl acetate:2/1), water was added to the mixture and the resulting
solid was filtered. The crude product was recrystallised from EtOH to yield (E)-
methyl 6-chloro-4-phenyl-2-styrylquinoline-3-carboxylate 2i as a brown solid
References and notes
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(0.327 g, 82%): mp 207–208 °C; IR (KBr): 1734 (C@O), 1209, 1062 cmÀ1
;
1H
NMR (300 MHz, DMSO-d6) 3.62 (s, 3H), 7.39–8.61 (m, 15H, 13 Ar–H + 2CH); 13
C
NMR (75 MHz, DMSO-d6) 53.2 (CH3), 122.1, 125.1, 126.5, 128.0, 128.3, 129.0,
129.5, 131.9, 132.2, 132.7, 134.3, 134.5, 143.1, 146.2, 150.3, 150.7, 167.1
(C@O); MS (EI, 70 eV): m/z (%): 399 (M+, 40), 384 (100), 323 (50); Anal.
Calcd for C25H18NO2Cl: C, 82.17; H, 5.24; N, 3.83. Found: C, 82.22; H, 5.19; N,
3.89.