A mild, efficient and improved protocol for the Friedlaender synthesis of quinolines using Lewis acidic ionic liquid

Article abstract of DOI:10.1002/jhet.5570410632

Lewis acidic ionic liquid is shown to be for the first time an excellent medium and efficient catalyst for the synthesis of quinolines at room temperature from o-amino aromatic carbonyls and ketones containing active methylene group.

Full text of DOI:10.1002/jhet.5570410632

Nov-Dec 2004 A Mild, Efficient and Improved Protocol for the Friedländer Synthesis
of Quinolines using Lewis acidic Ionic Liquid
1039
Ganesan Karthikeyan and Paramasivan T. Perumal∗
Organic Chemistry Division,
Central Leather Research Institute, Adyar, Chennai-600 020, INDIA
E-mail: ptperumal@hotmail.com; Fax: 91-44-24911589
Received May 21, 2004
Lewis acidic ionic liquid is shown to be for the first time an excellent medium and efficient catalyst for the
synthesis of quinolines at room temperature from o-amino aromatic carbonyls and ketones containing active
methylene group.
J. Heterocyclic Chem., 41, 1039 (2004).
Introduction.
The Friedländer condensation is still considered as the
most popular method, which provides rapid access to
quinolines and related aza aromatic compounds [1]. The
Figure 1
quinoline derivatives display wide range of biological
properties such as antiasthamatic [2], antiinflamatory [3],
The Lewis acidity of the Zinc chloride-1-butyl-3-methyl
imidazolium chloride molten melt (ZnCl -bmimCl) can be
and tyrosine kinase PDGF-RTF inhibiting properties [4].
The potent biological properties have naturally received
much attention of the synthetic community and several
reports on the synthesis of quinolines and substituted
quinolines have been described [5].
2
adjusted by varying the molar ratio of ZnCl to bmimCl in
2
the melts. Melts containing more than 33 mol% of ZnCl2
are considered to be acidic because there are not enough
chloride ions to fully co-ordinate with Zn(II) and, thus the
Zinc (II) species that are present in the melts might be the
Friedländer synthesis can be catalysed by strong acids or
bases or may take place without a catalyst at higher tem-
perature. The acidic catalysts used are conc. hydrochloric
acid, conc. sulfuric acid, p-toluenesulfonic acid and phos-
phoric acid and ZnCl [1b] Uncatalysed Friedländer syn-
−
−
coordinate unsaturated species like ZnCl , Zn Cl and
3
2
7
(
ZnCl ) which are chloride ion acceptors. In continuation
2 n
[12] of our interest in the application of room temperature
2
.
ionic liquids (RTILs) in organic synthesis, we reinvesti-
gated the Friedländer synthesis of quinolines by using
thesis usually requires more drastic reaction condition with
temperature in the range 150-220 °C. The synthetic scope
of this reaction however is reduced as a result of the harsh
reaction conditions and the use of strong acid or base cata-
lyst, which are incompatible with either acid or base sensi-
tive groups. Arcadi et al. [6a] reported a green approach
bmimCl:ZnCl melt (1:2 molar ratio ) that can act both as
2
a solvent and catalyst on account of its high polarity and
Lewis acidity.
Scheme 1
for the Friedländer synthesis using NaAuCl as a catalyst
4
and Levacher et al., [6b] described a novel traceless solid-
phase Friedländer synthesis. Recently, Palimkar et al. [6c]
have reported the synthesis of quinolines using ionic liquid
at higher temperature.
Room temperature ionic liquids (RTILs) have gained
popularity such as "green" alternative to conventional sol-
vents, due to several interesting properties [7] like negligi-
ble vapour pressure and wide liquid range.
Chloroaluminate ionic liquid has been reported as both
solvent and Lewis acid catalyst for Friedel-Crafts reaction
Results and Discussion.
o-Amino substituted aromatic ketones and 1,3 dicar-
bonyls (Scheme 1) were taken in bmimCl:ZnCl melt and
2
[
8] and Diels- Alder reaction [9]. Similar to the EMIC-
stirred at room temperature for 24 hr. to get quinolines (3a
-3m) [13] in good to excellent yields. The results are pre-
sented in Table-I. The reaction path suggested for the
Friedländer synthesis may involve sequential formation of
N-(o-acyl–phenyl )-β-enaminones/cyclodehydration reac-
tion. o-Aminobenzophenones react with ethyl acetoacetate
and acetyl acetone to give the corresponding quinolines
(3a, 3b) in 92% and 89 % yields. In the case of
AlCl system, the combination of anhydrous ZnCl and
3
2
EMIC have reported [10] to produce a low temperature
Lewis acidic molten salts. Recently, Davies and co-work-
ers [11a] synthesized Lewis acidic ionic liquids by mixing
appropriate molar ratio of MCl (M = Zn, Sn) with quater-
nary ammonium salts and employed it as a catalyst for the
Diels- Alder reaction [11b].
2

1
040
Communication to the Editor
Vol. 41
Table 1
Friedländer Synthesis of Quinolines using Lewis Acidic Ionic Liquid
o-aminoacetophenones, the corresponding quinoline were
synthesized in excellent yield (3e-88%, 3f-86%) which is
better in comparison with reported procedures [6a,6d].
When cyclic ketones were used as a carbonyl substrate the
reaction proceeded at room temperature giving the corre-
sponding qinolines in good yield. It is of interest to note
that the same reaction reported by Arcadi et al. required 60
ºC heating. Finally, this protocol was extended for the
reaction of 2-amino, 3-acyl benzofuran with ethyl acetoac-
etate giving the corresponding quinolines in 55% yield.
(
bmimCl:ZnCl2)
The reusability of bmimCl:ZnCl ionic liquid was stud-
2
ied and a marginal progressive loss in activity of ionic liq-
uid was found. The second and third run produce 3a in 89
and 86% yields.
Conclusion.
In conclusion, we have developed a simple and efficient
protocol for the effective synthesis of quinolines under
mild reaction conditions. This procedure neither requires
harsh reaction conditions nor the use of hazardous acids or
bases. We hope that this methodology will further widen
the use of Friedländer quinolines synthesis.
EXPERIMENTAL
General Experimental Procedure.
To bmimCl:ZnCl melt (0.35 g:0.55 g, heated at 90 ºC for 3 hr
2
under Ar atmosphere) was added acetyl acetone (0.2 g, 2 mmol)
and o-aminobenzophenone (0.197 g, 1 mmol) and stirred at room
temperature under Ar atmosphere for 24 hr. The reaction mixture
was extracted with diethyl ether (3 × 20 mL). The combined
organic layer was dried over anhydrous sodium sulphate, filtered
and concentrated under reduced pressure. The ionic liquid that
remained after ether extraction was dried under reduced pressure
and reused. The crude 3b thus obtained was purified by column
chromatography (ethyl acetate/petroleum ether, 5:95) to yield
1
%
-(2-methyl-4-phenylquinolin-3-yl)ethanone (3b): 0.234 g (88
); IR (Perkin Elmer, KBr): 1691 cm ; H NMR (JOEL,500
-
1 1
MHz, CDCl ): δ 1.98 (s, 3H, CH ), 2.68 (s, 3H, COCH ), 7.32-
3
3
3
7
8
.35 (m, 1H), 7.40 (m, 1H), 7.47 – 7.50 (m, 4H). 7.59 (d, 1H, J =
.0 Hz), 7.68 (m, 1H), 8.05 (d, 1H, J = 8 Hz); C NMR (125
1
3
MHz, CDCl ): δ 23.9, 32.0, 121.1, 126.2, 128.8, 128.9, 129.0,
3
1
30.1, 130.2, 134.9, 135.2, 144.0, 147.6, 153.6, 205.8; MS(JOEL
+
DX-303): m/z (relative intensity) 261 (47) [M ], 246 (100).
-1 1
Spectral data for 3c, 3i, 3m: 3c: IR (KBr): 1726 cm ; H NMR
500 MHz, CDCl ): δ 2.69 (s, 3H, CH ), 7.31-7.33 (m, 2H), 7.47-
(
3
3
7
=
.50 (m, 4H), 7.66(d, 1H, J = 8 Hz), 7.71 (m, 1H), 8.10 (d, 1H, J
1
3
8 Hz); C NMR (125 MHz, CDCl ): δ 23.9, 116.2 (q, J = 300
3
Hz), 124.5, 126.4, 127.2, 127.6, 128.7, 129.1, 129.5, 130.4,
1
31.4, 133.8, 147.5, 148.4, 153.4, 189.6 (q, J = 38 Hz); MS: m/z
+
(relative intensity) 315 (34) [M ], 246 (77), 218 (26), 70 (100).
-
1 1
3
i: IR (KBr): 3060, 2944, 1604 cm ; H NMR (500 MHz,
CDCl ): δ 1.77 (m, 2H), 1.95 (m, 2H), 2.59 (t, 2H, J = 6.9 Hz),
3
3
.20 (t, 2H, J = 6.85 Hz), 7.21 (d, 2H, J = 5.75 Hz), 7.28 – 7.32
(
m, 2H), 7.43 – 7.47 (m, 1H), 7.49 – 7.52 (t, 2H, J = 7.45 Hz),
a. All the products were identified by IR, NMR and MS. b. Isolated yield
after column chromatography. c. Reactions were carried out at 80° C. d.
Reaction done with 0.57 mmol of 1d.
1
3
7.57 – 7.62 (m, 1H), 8.01 (d, 1H, J = 8.0 Hz). C NMR (125
MHz, CDCl ): δ 22.9, 23.1, 34.2, 125.5, 125.8, 126.7, 127.8,
3

Nov-Dec 2004
Communication to the Editor
1041
1
28.3, 128.5, 128.7, 129.1, 137.1, 146.2, 146.7, 159.1; MS: m/z
Y. J. Im, Tetrahedron Lett., 43, 6209 (2002); [c] S. Cacchi, G. Fabrizi,
A. Goggiamni, M. Moreno-Manas, A. Vallribera, Tetrahedron Lett.,
43, 5537 (2002); [d] J.- Y. Legros, G. Primault, J.-C. Fiaud,
Tetrahedron, 57, 2507 (2001); [e] B. R. McNaughton, B. L. Miller,
Org Lett., 5, 4257 (2003); [f] D. S. Coffey, S.A. May and A. M. Ratz,
In Progress in Heterocyclic Chemistry, Vol. 13; G. W. Gribble, T. L.
Gilchrist, Eds.; Pergamon: London, 243, (2001); and the references
cited therein.
[6a] A. Arcadi, M. Chiarini, S. D. Giuseppe and F. Marinelli,
Synlett, 203 (2003); [b] C. Patteux, V. Levacher and G. Dupas, Org.
Lett 5, 3061 (2003); [c] S. S Palimkar, S. A. Siddiqui, T. Daniel, R.
J. Lahoti and K. V. Srinivasan, J. Org. Chem., 68, 9397 (2003); [d] G.
Kempter and G. Möbius, J. Prakt. Chem, 34, 298 (1996); [e] E. A.
Fehnel and D. E. Cohn, J. Org. Chem., 31, 3852 (1966); [f] E. A.
Fehnel and D. E. Cohn, J. Org. Chem. 31, 2899 (1966).
+
(relative intensity) 259 (44) [M ], 207 (43), 55(100). 3m: mp. 52º
-1 1
C IR (neat): 1728 cm ; H NMR (500 MHz, CDCl ): δ 1.40 (t,
3
4
3
H, J = 6.85 Hz CH2CH3), 2.53 (s, 3H, CH ), 2.68 (s, 3H, CH ),
3 3
.44 (q, 2H, J = 6.85 Hz), 7.33–7.34 (t, 1H, J = 8.0 Hz), 7.44-7.53
1
3
(m, 2H), 8.17 (d, 1H, J = 8.0 Hz); C NMR (125 MHz, CDCl3):
δ 12.7, 14.3, 23.2, 61.7, 112.0, 121.5, 123.2, 123.5, 127.3, 128.6,
1
2
5
42.9, 147.3, 151.2, 157.8, 168.4. MS: m/z (relative intensity)
+
69 (100) [M ]; Anal. Calcd for C H NO (269): C, 71.36; H,
.48; N, 5.85. Found: C, 71.40; H, 5.45; N, 5.90.
1
6
15
3
Acknowledgement.
One of the authors G.K thanks Council of Scientific and
Industrial Research, New Delhi for the financial support.
[
7a] T. Welton, Chem Rev, 99, 2071 (1999); [b] P.
Wasserscheid and K. Wilhelm, Angew. Chem. In. Ed., 39 3772,
2000); [c] R. Sheldon, Chem Commun., 2399, (2001).
8a] J. A. Boon, J. A. Levisky, J. L. Pflug and J. S. Wilkes, J.
REFERENCES AND NOTES
(
[
[
1a] C.-C. Cheng and S.-J. Yan, In Organic Reaction, Vol. 28;
Org. Chem. 51, 480 (1986); [b] M. J. Earle, P. B. McCormac and K.
R. Seddon, Green Chem., 2, 261 (2000); [c] J. K. D. Surette, L. Green
and R. D. Singer, Chem. Comm. 27, 53 (1996).
J. Wiley: New York, (1982), 37; and the references cited therein; [b]
A. Walser, T. Flynn and R. L. Fryer, J. Heterocyclic Chem., 12, 737
(1975); [c] P. G. Dormer, K. K. Eng, R. N. Farr, G. R. Humphery, J.
C. McWilliams, P. J. Reider, J. W. Sager and R. P. Volante, J. Org.
Chem. 467 (2003).
[9] C. W. Lee, Tetrahedron Lett., 40, 2461 (1999).
[10] P. -Y. Chen and I- W. Sun, Electrochimica Acta, 46, 1169
(2001).
[2] D. Doube, M. Blouin, C. Brideau, S. Desmarais, D. Ethier,
J. P. Falgueyret,
[11a] A. P. Abbott, G. Capper, D. L. Davies, H. Munro, R. K.
Rasheed and V. Tambyrajah, Chem. Comm., 2010 (2001); [b] A. P.
Abbott, G. Capper, D. L. Davies, R. K. Rasheed and V. Tambyrajah,
Green Chem., 4, 24 (2002).
R. W. Friesen, M. Girard, Y. Giraard, J. Guay, P. Tagari and R. N.
Young, Bioorg. Med. Chem. Lett. 8, 1255 (1998).
[3] B. Kalluraya and S. Sreevinasa, Farmaco 53, 399 (1998).
[
4] M. P. Maguire, K. R. Sheets, K. McVety, A. P. Spada and
[12] G. Karthikeyan and P. T. Perumal, Synlett, 2249 (2003).
[13] All compounds except 3m are known and exhibited
spectroscopic properties that agree with literature data according
to reference 6.
A. Zilberstein, J. Med. Chem. 37,2129, (1994).
5a] H. Z. S. Huma, R. Halder, S. S. Kaltra, J. Das and J. Iqbal,
Tetrahedron Lett., 43, 6485 (2002); [b] J. N. Kim, Y. M. Chung and
[