One-pot synthesis of 2-(2-hydroxyaryl)quinolines: Reductive coupling reactions of 2′-hydroxy-2-nitrochalcones

Article abstract of DOI:10.1016/S0040-4039(03)01374-1

A one-pot synthesis of novel 2-(2-hydroxyaryl)quinolines have been developed from the intramolecular reductive coupling reactions of 2′-hydroxy-2-nitrochalcones, induced by stannous chloride in acidic medium (HCl/AcOH). In some cases these transformations can be performed with ammonium formate/Pd-C in methanol.

Full text of DOI:10.1016/S0040-4039(03)01374-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5893–5896
One-pot synthesis of 2-(2-hydroxyaryl)quinolines: reductive
coupling reactions of 2%-hydroxy-2-nitrochalcones
Ana I. R. N. A. Barrosa and Artur M. S. Silvab,*
aChemistry Department, University of Tra´s-os-Montes e Alto Douro, 5001-911 Vila Real, Portugal
bChemistry Department, University of Aveiro, 3810-193 Aveiro, Portugal
Received 24 May 2003; revised 27 May 2003; accepted 2 June 2003
Abstract—A one-pot synthesis of novel 2-(2-hydroxyaryl)quinolines have been developed from the intramolecular reductive
coupling reactions of 2%-hydroxy-2-nitrochalcones, induced by stannous chloride in acidic medium (HCl/AcOH). In some cases
these transformations can be performed with ammonium formate/Pd–C in methanol.
© 2003 Elsevier Ltd. All rights reserved.
Quinolines are six-membered heterocyclic compounds
widely distributed in nature.1 Due to the interesting and
important biological properties and applications of
quinoline derivatives (such as pharmaceuticals, poly-
mers, cyanine dyes, antioxidants in the rubber industry
and fungicides) many syntheses are reported in the
literature for this type of compounds,2 however the
development of new and efficient methods for the
preparation of these important molecules still continues
to be an important and attractive area of research in
synthetic organic chemistry.3,4 In continuation of our
interest in heterocyclic molecules,5 we herein report a
simple and facile one-pot synthesis of novel 2-(2-
hydroxyaryl)quinolines 3 from 2%-hydroxy-2-nitro-chal-
cones 1.
tions of allylic alcohols or acetylenic carbinols with
iodoanilines, from ruthenium-catalysed carbonylation
of 2-nitrochalcones and from reductive coupling reac-
tions of 2-nitrochalcones with low-valent titanium
reagent (TiCl4/Sm).9 Some of these known methods for
the synthesis of 2-arylquinolines have some disadvan-
tages such as harsh reaction conditions, laborious
work-up and low yields. To our best knowledge there
are no reports on the synthesis of 2-(2-hydroxy-
aryl)quinolines, which can be used as good bidentate
ligands in the complexation of transition metal ions.
Here we report the first synthesis of 2-(2-hydroxy-
aryl)quinolines 3a–d from the intramolecular reductive
coupling reactions of the corresponding 2%-hydroxy-2-
nitrochalcones 1a–d induced by stannous chloride in
hydrochloric acid and in some cases with ammonium
formate–Pd/C in methanol.
In the last decade, the cyclisation of 2%-aminochalcones
has been stimulated since it originates 2-aryl-4-
quinolone derivatives2,6,7 which present important phar-
macological activities.7,8 More recently 2%-amino-
chalcones have been used in the preparation of 2-aryl-4-
chloro-N-formyl-1,2-dihydroquinolines from their cycli-
sation under Vilsmeier conditions.4 During our ongoing
research program on the synthesis of aminochalcones
and knowing that some quinolines can be made by
intramolecular reactions of amino with carbonyl
groups,9,10 we decided to study the reduction of 2%-
hydroxy-2-nitrochalcones 1. 2-Aryl-quinolines have
been obtained from palladium-catalysed coupling reac-
The treatment of 2%-hydroxy-2-nitrochalcones 1a–d with
an excess of hydrated stannous chloride in hydrochloric
acid led, after work-up, to the formation of two com-
pounds when starting with chalcones 1a,b and only one
in the case of chalcones 1c,d11 (revealed by TLC analy-
sis of the reaction mixture) (Scheme 1). The main
spectroscopic characteristics of the product obtained in
both cases are: (i) the presence of a hydroxyl group
involved in a strong hydrogen bond (lH 14.93–15.34
ppm in the 1H NMR spectra); (ii) the absence of double
bonds in a trans configuration, well established in the
1H NMR spectra of chalcones;12 (iii) the absence of
carbonyl groups in the 13C NMR spectra; and (iv)
Keywords: 2-(2-hydroxyaryl)quinolines; 2-(2-hydroxyaryl)quinolines-
N-oxides; 2%-hydroxy-2-nitrochalcones; reduction; cyclodehydration.
* Corresponding author. Tel.: +351 234 370 714; fax: +351 234 370
084; e-mail: arturs@dq.ua.pt
molecular ions (M+ in the EIMS) corresponding to the
’
reduction of the nitro substituent into the amino group
and the loss of one water molecule. All these spectro-
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01374-1

5894
A. I. R. N. A. Barros, A. M. S. Sil6a / Tetrahedron Letters 44 (2003) 5893–5896
Scheme 1.
scopic data support the structure of novel 2-(2-hydroxy-
aryl)quinolines 3a–d.13 The second product obtained
when starting with chalcones 1a,b present similar spec-
troscopic features to those of 3a–d, but the hydroxyl
group involved in an hydrogen bond appear at lower
3c,d. In the case of starting with 4%-benzyloxy-2%-
hydroxy-2-nitro-chalcone 1d there also was the cleavage
of the benzyloxy group, due to the presence of hydro-
chloric
acid,
giving
the
2-(2,4-dihydroxy-
phenyl)quinoline 3d.16 The reduction of intermediates
5a,b into the corresponding 2-amino-chalcones 4a,b is
probably slower and allowed the intramolecular attack
of the hydroxylamine to the carbonyl group yielding
intermediates 6a,b which can then be reduced to the
novel 2-(2-hydroxyaryl)quinoline-N-oxides 2a,b.
1
frequency values (lH 11.30–11.37 ppm in the H NMR
spectra) and the molecular ions (M+ in the EIMS)
’
presents more 16 u.m.a. These data are only compatible
with the structure of novel 2-(2-hydroxyaryl)quinoline-
N-oxides 2a,b.14
The results described above can be envisaged by the
reaction mechanism depicted in Scheme 2: One of the
intermediates in the reduction of 2-nitrochalcones 1 are
hydroxylamine derivatives 5.15 In the case of electron
donating substituents in the A ring (other than the OH
involved in the intramolecular hydrogen bond) the
reduction of these hydroxylamine derivatives 5c,d into
the 2-aminochalcones 4c,d is favoured and followed by
their acid-catalysed cyclodehydration into quinolines
The treatment of 2%-hydroxy-2-nitrochalcones 1c,d with
ammonium formate and Pd/C in methanol at room
temperature for 3 h gave the corresponding aminochal-
cones 4c,d (Scheme 1).17,18 This means that in these
conditions only the reduction of the nitro substituents
occur; there was no reduction of the chalcone double
bond and the benzyloxy group was not cleaved. How-
ever, the treatment of 2%-hydroxy-2-nitrochalcones 1a,b
with ammonium formate and Pd/C in the same condi-
Scheme 2.

A. I. R. N. A. Barros, A. M. S. Sil6a / Tetrahedron Letters 44 (2003) 5893–5896
5895
tions yielded a mixture 2-(2-hydroxyaryl)quinolines
3a,b (33–37%) and 2-(2-hydroxyaryl)quinoline-N-oxides
2a,b (36–39%). These results confirm our hypothesis on
the formation of quinoline-N-oxides 2a,b in the reduc-
tion of nitrochalcones 1a,b. The reduction of hydroxyl-
amine derivatives 5a,b is very slow, allowing the forma-
tion of intermediates 6a,b and their reduction to quino-
line-N-oxides 2a,b, which can be reduced in these
reaction conditions to the corresponding quinolines
3a,b. This fact was confirmed by performing the reduc-
tion of quinoline-N-oxides 2a,b into quinolines 3a,b
with ammonium formate and Pd/C in methanol at
room temperature.
8. (a) Hirak, U.; Hisashi, Y.; Hiroshi, Y.; Hitoshi, T. Eur.
Pat. Appl. EP 287951, Chem. Abstr. 1989, 110, 173109k;
(b) Osawa, T.; Ohta, H.; Akimoto, K.; Harada, K.; Soga,
H.; Jinno, Y. Eur. Pat. Appl. EP 343547, Chem. Abstr.
1990, 112, 235197g.
9. (a) Larock, R. C.; Kuo, M.-Y. Tetrahedron Lett. 1991,
32, 569–572; (b) Kundu, N. G.; Mahanty, J. S.; Das, P.;
Das, B. Tetrahedron Lett. 1993, 34, 1625–1628; (c)
Cenini, S.; Bettettini, E.; Fedele, M.; Tollari, S. J. Mol.
Catal. A: Chem. 1996, 111, 37–41; (d) Ma, Y.; Zhang, Y.
J. Chem. Res. 2001, 108–109.
10. Boix, C.; de la Fuente, J. M.; Poliakoff, M. New J. Chem.
1999, 23, 641–643.
11. Typical procedure with SnCl2·2H2O in HCl/AcOH: A
solution of hydrated stannous chloride (5.2 g, 23 mmol)
in concentrated hydrochloric acid (20 mL) was added to
a suspension of the appropriate 2%-hydroxy-2-nitrochal-
cone 1a–d (5.7 mmol) in acetic acid (60 mL). The mixture
was heated at 90°C for 4 h. After that period, the
solution was cooled and treated with an excess of a 25%
aqueous sodium hydroxide solution. The residue
obtained was extracted with chloroform (2×50 mL) dried
over Na2SO4 and evaporated to dryness. In the case of
In conclusion we established a new one-pot synthesis of
novel 2-(2-hydroxyaryl)quinolines from intramolecular
reductive coupling reactions of 2%-hydroxy-2-nitro-chal-
cones. The application of this approach to the synthesis
of other 2-arylquinolines in ongoing and will be
reported in due course.
Acknowledgements
4%-substituted-2%-hydroxy-2-nitrochalcones
1c,d,
the
residue was purified by silica gel column chromatogra-
phy, using chloroform as eluent, giving after evaporation
and recrystallisation from ethanol 2-(2-hydroxy-
aryl)quinolines 3c,d (3c, 66%; 3d, 58%). For 2%-hydroxy-2-
nitrochalcones 1a,b, the obtained residue was purified by
silica gel column chromatography, using as eluent 1:3 and
1:1 mixtures of chloroform-light petroleum to respec-
tively collect 2-(2-hydroxyaryl)quinolines 3a,b and 2-(2-
hydroxyaryl)quinoline-N-oxides 2a–b (2a, 47%; 3a, 23%;
2b, 44%; 3b, 27%).
Thanks are due to the University of Aveiro, University
of Tra´s-os-Montes e Alto Douro and FCT-Portugal
(Organic Chemistry Research Unit) for funding.
References
1. Balasubramanian, M.; Keay, J. G. In Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R.; Rees, C. W.;
Scriven, E. F., Eds.; Pergamon: Oxford, 1996; Vol. 5, pp.
245–300 and references cited therein.
2. Jones, G. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F., Eds.;
Pergamon: Oxford, 1996; Vol. 5, pp. 167–243 and refer-
ences cited therein.
12. (a) Silva, A. M. S.; Tavares, H. R.; Barros, A. I. N. R.
A.; Cavaleiro, J. A. S. Spectrosc. Lett. 1997, 30, 1655–
1667; (b) Silva, A. M. S.; Cavaleiro, J. A. S.; Tarrago, G.;
Marzin, C. New J. Chem. 1999, 23, 329–335; (c) Pinto, D.
C. G. A.; Silva, A. M. S.; Cavaleiro, J. A. S.; Elguero, J.
Eur. J. Org. Chem. 2003, 747–755.
3. (a) Meth-Cohn, O.; Goon, S. J. Chem. Soc., Perkin
Trans. 1 1997, 85–89; (b) Katritzky, A. R.; Arend, M. J.
Org. Chem. 1998, 63, 9989–9991; (c) Kouznetsov, V.;
Palma, A.; Ewert, C.; Varlamov, A. J. Heterocycl. Chem.
1998, 35, 761–785; (d) Basavaiah, D.; Reddy, R. M.;
Kumaragurubaran, N.; Sharada, D. S. Tetrahedron 2002,
58, 3693–3697.
13. Spectroscopic data for 2-(2-hydroxyphenyl)quinoline 3a:
1
mp: 109.8–110.7°C; H NMR (300.13 MHz, DMSO-d6):
l 6.97–7.03 (m, 2H, H-3% and H-5%), 7.41 (dt, 1H, H-4%,
J=1.2 and 7.7 Hz), 7.67 (dt, 1H, H-6, J=0.7 and 7.7
Hz), 7.85 (dt, 1H, H-7, J=1.1 and 7.7 Hz), 8.05–8.10 (m,
2H, H-5 and H-8), 8.22 (dd, 1H, H-6%, J=1.2 and 7.7
Hz), 8.39 (d, 1H, H-3, J=8.9 Hz), 8.59 (d, 1H, H-4,
J=8.9 Hz), 14.93 (s, 1H, OH); 13C NMR (75.47 MHz,
DMSO-d6): l 118.0 (C-3 and C-3%), 118.8 (C-1%), 118.9
(C-5%), 126.4 (C-4a), 127.0 (C-6 and C-8), 127.9 (C-6%),
128.0 (C-5), 130.9 (C-7), 132.2 (C-4%), 138.4 (C-4), 144.1
4. Akila, S.; Selvi, S.; Balasubramanian, K. Tetrahedron
2001, 57, 3465–3469.
5. (a) Pinto, D. C. G. A.; Silva, A. M. S.; Cavaleiro, J. A.
S. New J. Chem. 2000, 24, 85–92; (b) Pinto, D. C. G. A.;
Silva, A. M. S.; Le´vai, A.; Cavaleiro, J. A. S.; Patonay,
T.; Elguero, J. Eur. J. Org. Chem. 2000, 2593–2599; (c)
Pinto, D. C. G. A.; Silva, A. M. S.; Almeida, L. M. P.
M.; Cavaleiro, J. A. S.; Elguero, J. Eur. J. Org. Chem.
2002, 3807–3815; (d) Sandulache, A.; Silva, A. M. S.;
Cavaleiro, J. A. S. Tetrahedron 2002, 58, 105–114.
6. (a) Donnelly, J. A.; Farrell, D. F. J. Org. Chem. 1990, 55,
1757–1761; (b) Varma, R. S.; Saini, R. K. Synlett 1997,
857–858.
(C-8a), 157.7 (C-2), 160.2 (C-2%); EI-MS: m/z (rel. inten-
+
’
sity) 221 (M , 100), 220 (59), 193 (25), 180 (15), 167 (30),
154 (7), 128 (16), 111 (8), 96 (10), 89 (4), 84 (15), 77 (9),
63 (7). Anal. calcd for C15H11NO: C, 81.45; H, 4.98; N,
6.33. Found: C, 81.40; H, 5.02; N, 6.30%.
14. Spectroscopic data for 2-(2-hydroxyphenyl)quinoline-N-
oxide 2a: mp: 180.3–181.0°C; 1H NMR (300.13 MHz,
DMSO-d6): l 7.05 (dd, 1H, H-3%, J=1.0 and 7.7 Hz), 7.10
(dt, 1H, H-5%, J=1.0 and 7.7 Hz), 7.53 (dt, 1H, H-4%,
J=1.6 and 7.7 Hz), 7.69 (dd, 1H, H-6%, J=1.6 and 7.7
Hz), 7.87 (dt, 1H, H-6, J=1.0 and 7.8 Hz), 7.96 (d, 1H,
H-3, J=8.9 Hz), 8.01–8.04 (m, 1H, H-7), 8.25 (d, 1H,
7. Xia, Y.; Yang, Z.-Y.; Xia, P.; Hackl, T.; Hamel, E.;
Mauger, A.; Wu, J.-H.; Lee, K.-H. J. Med. Chem. 2001,
44, 3932–3936.

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A. I. R. N. A. Barros, A. M. S. Sil6a / Tetrahedron Letters 44 (2003) 5893–5896
H-5, J=7.8 Hz), 8.35 (d, 1H, H-4, J=8.9 Hz), 8.75 (d,
nium formate (23 mmol) in a single portion under nitro-
gen atmosphere. The resulting mixture was stirred at
room temperature for 3 h. The catalyst was removed by
filtration through Celite pad and washed with methanol
(2×10 mL). The filtrate was evaporated under reduced
pressure and the residue dissolved in chloroform and
washed with water (3×25 mL). The organic layer was
dried over Na2SO4 and evaporated to dryness. In the case
of 4%-substituted-2%-hydroxy-2-nitrochalcones 1c,d, the
residue was recrystallised from ethanol, giving 2-amino-
2%-hydroxychalcones 4c,d (4c, 68%; 4d, 50%). For 2%-
hydroxy-2-nitrochalcones 1a,b, the obtained residue was
purified by silica gel column chromatography, using as
eluent 1:3 and 1:1 mixtures of chloroform-light petroleum
to respectively collect 2-(2-hydroxyaryl)quinolines 3a,b
and 2-(2-hydroxyaryl)quinoline-N-oxides 2a–b (2a, 36%;
3a, 33%; 2b, 39%; 3b, 37%).
1H, H-8, J=8.7 Hz), 11.30 (s, 1H, OH); 13C NMR (75.47
MHz, DMSO-d6): l 119.0 (C-8), 119.6 (C-3%), 120.0 (C-
5%), 121.4 (C-1%), 124.7 (C-3), 128.7 (C-5), 128.8 (C-4a),
129.2 (C-6), 130.2 (C-4), 132.1 (C-6%), 132.2 (C-7), 132.4
(C-4%), 139.9 (C-8a), 147.6 (C-2), 159.1 (C-2%); EI-MS: m/z
’
(rel. intensity) 237 (M+ , 48), 221 (32), 220 (100), 208 (7),
191 (20), 180 (15), 165 (14), 140 (5), 128 (9), 102 (3), 95
(6), 77 (5), 63 (4). Anal. calcd for C15H11NO2: C, 75.95;
H, 4.64; N, 5.91. Found: C, 81.40; H, 5.02; N, 6.30%.
15. Roberts, J. S. In Comprehensive Organic Chemistry; Bar-
ton, D.; Ollis, W. D., Eds.; Pergamon: Oxford, 1979; Vol.
2, pp. 184–217.
16. Spectroscopic data for 2-(2,4-dihydroxyphenyl)quinoline
1
3d: mp: 175.4–176.3°C; H NMR (300.13 MHz, DMSO-
d6): l 6.36 (d, 1H, H-3%, J=2.4 Hz), 6.43 (dd, 1H, H-5%,
J=2.4 and 8.7 Hz), 7.59 (dt, 1H, H-6, J=0.9 and 8.0
Hz), 7.76–7.82 (m, 1H, H-7), 7.96 (d, 1H, H-8, J=8.0
Hz), 7.99 (d, 1H, H-5, J=8.0 Hz), 8.02 (d, 1H, H-6%,
J=8.7 Hz), 8.21 (d, 1H, H-3, J=9.0 Hz), 8.47 (d, 1H,
H-4, J=9.0 Hz), 10.03 (s, 1H, OH-4%), 15.23 (s, 1H,
OH-2%); 13C NMR (75.47 MHz, DMSO-d6): l 103.5
(C-3%), 107.5 (C-5%), 110.8 (C-1%), 117.5 (C-3), 125.8 (C-
4a), 126.3 (C-6), 126.5 (C-8), 128.0 (C-5), 129.2 (C-6%),
130.8 (C-7), 138.0 (C-4), 144.0 (C-8a), 158.0 (C-2), 161.2
18. Spectroscopic data for 2%-amino-4%-methoxychalcone 4c:
mp: 156.7–157.9°C; 1H NMR (300.13 MHz, CDCl3): l
3.86 (s, 3H, OCH3), 4.09 (s, 2H, NH2), 6.47 (s, 1H, H-3%),
6.50 (dd, 1H, H-5%, J=2.5 and 9.6 Hz), 6.74 (d, 1H, H-3,
J=7.6 Hz), 6.81 (t, 1H, H-5, J=7.6 Hz), 7.22 (dt, 1H,
H-4, J=1.2 and 7.6 Hz), 7.50 (d, 1H, H-6, J=7.6 Hz),
7.51 (d, 1H, H-a, J=15.2 Hz), 7.82 (d, 1H, H-6%, J=9.6
Hz), 8.05 (d, 1H, H-b, J=15.2 Hz), 13.52 (s, 1H, OH);
13C NMR (75.47 MHz, CDCl3): l 55.6 (OCH3), 101.0
(C-3%), 107.7 (C-5%), 114.1 (C-1%), 116.9 (C-3), 118.9 (C-5),
120.1 (C-a), 120.2 (C-1), 128.2 (C-6), 131.2 (C-6%), 131.8
’
(C-4%), 162.4 (C-2%); EI-MS: m/z (rel. intensity) 237 (M+ ,
92), 236 (64), 207 (33), 191 (3), 180 (36), 167 (9), 128 (12),
105 (100), 89 (11), 77 (67), 63 (15). Anal. calcd for
C15H11NO2: C, 75.95; H, 4.64; N, 5.91. Found: C, 81.40;
H, 5.02; N, 6.30%.
(C-4), 139.7 (C-b), 146.3 (C-2), 166.1 (C-4%), 166.7 (C-2%),
’
191.8 (CꢀO); EI-MS: m/z (rel. intensity) 269 (M+ , 27),
252 (62), 251 (100), 250 (38), 222 (8), 208 (11), 180 (10),
151 (33), 146 (16), 128 (15), 118 (34), 108 (12), 91 (17).
Anal. calcd for C16H15NO3: C, 71.38; H, 5.58; N, 5.20.
Found: C, 81.40; H, 5.02; N, 6.30%.
17. Typical procedure HCO2NH4, Pd/C. To a stirred suspen-
sion of the appropriate 2%-hydroxy-2-nitrochalcone 1a–d
(5 mmol) and 10% Pd/C (0.2–0.3 g) in dry methanol (10
mL) at room temperature was added anhydrous ammo-