Novel method of synthesis of 2,3-dihydro-furo[3,2-h]quinolines

Article abstract of DOI:10.1007/s10593-012-1090-3

Reaction of 8-hydroxy-7-piperidinomethylquinoline with pyridinium ylides gave 2-acyl-2,3-dihydro-furo[3,2-h]quinolines. The formation of a highly electrophilic quinoline type o-quinone methide is proposed as an intermediate.

Full text of DOI:10.1007/s10593-012-1090-3

Chemistry of Heterocyclic Compounds, Vol. 48, No. 7, October, 2012 (Russian Original Vol. 48, No. 7, July, 2012)
NOVEL METHOD OF SYNTHESIS OF 2,3-DIHYDRO-
FURO[3,2-h]QUINOLINES
V. A. Osyanin1*, D. V. Osipov1, and Yu. N. Klimochkin1
Reaction of 8-hydroxy-7-piperidinomethylquinoline with pyridinium ylides gave 2-acyl-2,3-dihydro-
furo[3,2-h]quinolines. The formation of a highly electrophilic quinoline type o-quinone methide is
proposed as an intermediate.
Keywords: 1,2-dihydrofuro[3,2-h]quinolines, pyridinium ylides, o-quinolone methides, Mannich bases.
2,3-Dihydrofuro[3,2-h]quinolines are of interest as inhibitors of aldose reductase [1] and as antimalaria
agents [2], but there are a few effective methods for their preparation [3-7]. For instance, a method is known for
obtaining 2,3-dihydrofuran systems in the reaction of 2-hydroxy-,-unsaturated ketones with sulfur ylides,
with the principal formation of a trans isomer [8]. Treatment of substituted 2-arylidenepropane-1,3-diones with
pyridinium ylides gives a broad range of 2,3-dihydrofurans [9, 10]. However, these methods are limited by the
choice of starting substrate, and this does not allow a direct preparation of benzo-condensed 2,3-dihydrofuran
systems.
O
N+
N
N
Br–
R
2a–c
OH
O
R
O
TMG
MeCN, 
N
3a–c
– Py
1
– C5H10NH
N
N
O–
COR
O
2a–c
+
N
TMG
CH2
A
a R = t-Bu, b R = 1-adamantyl, c R = cyclopropyl
_______
*To whom correspondence should be addressed, e-mail: VOsyanin@mail.ru.
1Samara State Technical University, 244 Molodogvardeiskaya St., Samara 443100, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1069-1072 , July, 2012. Original
article submitted May 16, 2011.
0009-3122/12/4807-0993©2012 Springer Science+Business Media New York
993

In continuing our study of the synthetic potential of o-quinone methides in the construction of oxygen-
containing heterocycles [11, 12], we have developed a single-stage method for preparing the 2-acyl-2,3-di-
hydrofuro[3,2-h]quinolines 3a-c through a reaction of 8-hydroxy-7-piperidinomethylquinoline (1) with
pyridinium ylides generated in situ from the pyridinium salts 2a-c using 1,1,3,3-tetramethylguanidine (TMG) in
refluxing acetonitrile under an inert atmosphere.
This process apparently involves generation of the highly electrophilic o-quinolone methide A, which
reacts with the ylide at the carbon atom. Subsequent intramolecular nucleophilic substitution is accompanied by
cleavage of a pyridine molecule to give the corresponding 2,3-dihydrofuro[3,2-h]quinolines 3a-c. Formation of
the products of a potential cyclopropanation B [8, 13] of exocyclic double bond in the o-quinolone methide A
was not observed. The dipolar nature of the ylides, generally shown in reactions with electron-deficient alkenes
[14], was not revealed in this case. This is evidently related to the unfavored simultaneous loss of aromaticity in
the benzene and pyridine rings upon formation of the spiro ketones C, which is not the case with the products
3a-c.
O
O
N
N
N
TMG
TMG
1
+
2a–c
R
R
O
O
B
C
The reaction of Mannich base 1 with 4-bromophenacyl pyridinium bromide (2d) under an argon
atmosphere mainly gave the aromatization product, namely, furo[3,2-h]quinoline 4, evidently formed by
oxidation of the corresponding dihydrofuro[3,2-h]quinoline during the isolation. The high tendency towards
oxidation is related to the delocalized chain of conjugation involving the benzene ring.
N
O
O
O
N+
Br–
TMG, O2
1
+
– Py
– H2O
Br
2d
4
Br
In the 1H NMR spectra of compounds 3a-c, the H-2 proton signal of the dihydrofuran ring is seen in the
5.43-5.77 ppm region as a double doublet due to a vicinal splitting by the methylene group protons. The latter
also appear as double doublets at 3.42-3.70 ppm. In the 13C NMR spectra of the dihydrofuroquinolines 3a-c, the
carbonyl carbon signals are found in the region of 210.0-211.4 ppm, and the C-2 and C-3 signals appear at
81.1-86.9 and 34.2-34.7 ppm, respectively.
Hence we have demonstrated the potential of o-quinolone methides in reaction with in situ generated
pyridinium ylides, to form benzo-condensed 2,3-dihydrofuran systems. As an example, we report a convenient
method for the preparation of 2,3-dihydrofuro[3,2-h]quinoline derivatives.
EXPERIMENTAL
1
IR spectra were recorded on a Shimadzu FTIR-8400S spectrometer in KBr pellets. H and 13C NMR
spectra were recorded on a JEOL JNM-ECX400 spectrometer (400 and 100 MHz, respectively) using CDCl3
with TMS as internal standard. Mass spectra were recorded on a Finnigan Trace DSQ instrument with 70 eV
electron ionization energy. Elemental analysis was performed on an automatic EuroVector Euro EA 3000
CHNS analyzer. Melting points were recorded by the capillary method on a PTP-M instrument.
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1-(2,3-Dihydrofuro[3,2-h]quinolin-2-yl)-2,2-dimethyl-1-propanone (3a). 1,1,3,3-Tetramethylguani-
dine (0.52 ml, 0.47 g, 4.1 mmol) was added to a mixture of 8-hydroxy-7-piperidinomethylquinoline (1) [15]
(1.00 g, 4.1 mmol) and 1-(3,3-dimethyl-2-oxobutyl)pyridinium bromide (2a) [16] (1.06 g, 4.1 mmol) in MeCN
(15 ml). The solution obtained was refluxed for 5 h under an argon atmosphere. The solvent was evaporated in
vacuo, the residue was treated with MeOH (5 ml), and the mixture was held for 1 day at -20ºC. The precipitate
was filtered off, washed with cold MeOH, and recrystallized from EtOH. Yield 0.44 g (42%). Colorless crystals,
mp 112-113ºC. IR spectrum, , cm-1: 2974, 2951, 2866, 1717(C=O), 1512, 1462, 1396, 1362, 1315, 1288, 1080,
930, 837, 783. 1H NMR spectrum, , ppm (J, Hz): 1.27 (9H, s, C(CH3)3); 3.47 (1H, dd, 2J = 15.6, 3J = 7.8) and
2
3
3
3
3.59 (1H, dd, J = 15.6, J = 10.5, CH2); 5.73 (1H, dd, J = 10.5, J = 7.3, CH); 7. 28-7.31 (3H, m, H-4,5,7);
3
4
3
4
13
8.05 (1H, dd, J = 8.2, J = 1.4, H-6); 8.82 (1H, dd, J = 4.1, J = 1.4, H-8). C NMR spectrum, , ppm: 26.2
(CH3); 34.7 (CH2); 43.8 (C); 82.1 (CH); 120.6 (CH); 121.1 (CH); 123.2 (C); 123.2 (CH); 129.0 (C); 135.8 (C);
136.0 (CH); 150.0 (CH); 154.5 (C); 211.4 (C=O). Mass spectrum, m/z (Irel, %): 255 [M]+ (7), 198 [M-C(CH3)3]+
(15), 170 [M-(CH3)3CCO]+ (100), 142 (33), 115 (8), 57 [C(CH3)3]+ (13). Found, %: С 75.35; Н 6.77; N 5.41.
C16H17NO2. Calculated, %: C 75.27; H 6.71; 5.49.
1-Adamantyl-2,3-dihydrofuro[3,2-h]quinolin-2-ylmethanone (3b) was prepared similarly to
compound 3a from compound 1 (1.00 g, 4.1 mmol), 1-[2-(1-adamantyl)-2-oxoethyl]pyridinium bromide (2b)
[17] (1.39 g, 4.1 mmol), and 1,1,3,3-tetramethylguanidine (0.52 ml, 0.47 g, 4.1 mmol). Yield 0.76 g (55%).
Colorless crystals, mp 174-175ºC (EtOH). IR spectrum, , cm-1: 2901, 2851 (CHAd); 1705 (C=O), 1512, 1466,
1362, 1312, 1285, 1165, 1080, 1011, 922, 829. 1H NMR spectrum, , ppm (J, Hz): 1.69-1.76 (6H, m, CH2 Ad);
2
3
1.90-1.98 (6H, m, CH2 Ad); 2.05 (3H, br. s, CH Ad); 3.42 (1H, dd, J = 15.6, J = 7.6) and 3.57 (1H, dd,
3
3
3
2J = 15.6, J = 10.5, CH2); 5.77 (1H, dd, J = 10.5, J = 7.6, CH); 7.26-7.30 (3H, m, H-4,5,7); 8.06 (1H, dd,
3J = 8.2, J = 1.4, H-6); 8.82 (1H, dd, J = 4.1, J = 1.4, H-8). 13C NMR spectrum, , ppm: 27.8 (CH); 34.6
(CH2); 36.5 (CH2); 37.8 (CH2); 45.9 (C); 81.1 (CH); 120.5 (CH); 121.1 (CH); 123.0 (C); 123.2 (CH); 129.0 (C);
135.8 (C); 136.0 (CH); 150.0 (CH); 154.7 (C); 210.0 (C=O). Mass spectrum, m/z (Irel, %): 333 [M]+ (5), 198
[M-Ad]+ (22), 197 [M-H-Ad]+ (15), 170 [M-AdCO]+ (100), 169 [M-AdCO-H]+ (40), 142 (25), 135 [Ad]+ (90).
Found, %: С 79.16; Н 7.02; N 4.26. C22H23NO2. Calculated, %: C 79.25; H 6.95; N 4.20.
4
3
4
Cyclopropyl-2,3-dihydrofuro[3,2-h]quinolin-2-ylmethanone (3c) was prepared similarly to
compound 3a from compound 1 (1.00 g, 4.1 mmol), 1-(2-cyclopropyl-2-oxoethyl)pyridinium bromide 2c [18]
(1.00 g, 4.1 mmol), and 1,1,3,3-tetramethylguanidine (0.52 ml, 0.47 g, 4.1 mmol). Yield 0.34 g (34%).
Colorless crystals, mp 80-82ºC (Et2O). IR spectrum, , cm-1: 3005, 2920, 1701 (C=O), 1512, 1466, 1389, 1362,
1
1319, 1288, 1122, 1076, 972, 945, 829, 791. H NMR spectrum, , ppm (J, Hz): 0.90-0.96 (1H, m,
cyclopropyl); 1.00-1.18 (3H, m, cyclopropyl); 2.63-2.69 (1H, m, cyclopropyl); 3.60 (1H, dd, 2J = 16.0, 3J = 7.4)
2
3
and 3.70 (1H, dd, J = 16.0, J = 11.0, CH2); 5.43 (1H, dd, 3J = 11.0, 3J = 7.4, CH); 7.36-7.40 (3H, m, H-4,5,7);
4
3
4
8.14 (1H, dd, 3J = 8.2, J = 1.8, H-6); 8.89 (1H, dd, J = 4.6, J = 1.8, H-8). 13C NMR spectrum, , ppm: 12.6
(CH2); 13.0 (CH2); 16.7 (CH); 34.2 (CH2); 86.9 (CH); 120.9 (CH); 121.2 (CH); 123.4 (CH); 123.6 (C); 129.0
(C); 135.9 (C); 136.2 (CH); 150.2 (CH); 154.3 (C); 210.4 (C=O). Mass spectrum, m/z (Irel, %): 239 [M]+ (4),
198 [M-C3H5]+ (1), 170 [M-C3H5CO]+ (100), 142 (26), 115 (9), 69 [C3H5CO]+ (5). Found, %: С 75.39; Н 5.54;
N 5.76. C15H13NO2. Calculated, %: C 75.30; H 5.48; N 5.85.
4-Bromophenylfuro[3,2-h]quinolin-2-ylmethanone (4). 1,1,3,3-Tetramethylguanidine (0.52 ml,
0.47 g, 4.1 mmol) was added to a mixture of compound 1 (1.00 g, 4.1 mmol), 1-[2-(4-bromophenyl)-2-oxo-
ethyl]pyridinium bromide 2d [19] (1.47 g, 4.1 mmol) in MeCN (20 ml), and the solution obtained was refluxed
for 10 h with vigorous stirring in the presence of atmospheric oxygen. Solvent was evaporated in vacuo, and the
residue was treated with cold MeOH (5 ml) and held at -20ºC for 1 day. The precipitate was filtered off, washed
with cold MeOH, and recrystallized from EtOH. Yield 0.51 g (35%). Pale-yellow crystals, mp 167-168ºC. IR
spectrum, , cm-1: 3082, 2924, 1639 (C=O), 1582, 1539, 1508, 1373, 1323, 1300, 1119, 968, 899, 829, 752. 1H
NMR spectrum, , ppm (J, Hz): 7.50 (1H, dd, 3J = 8.2, 3J = 4.4, H-7); 7.65 (1H, d, 3J = 8.5, H-5); 7.67 (2H, d,
3
3
3J = 8.7, H-3',5'); 7.73 (1H, s, H-3); 7.75 (1H, d, J = 8.5, H-4); 8.06 (2H, d, J = 8.7, H-2',6'); 8.23 (1H, dd,
3J = 8.2, J = 1.6, H-6); 9.00 (1H, dd, J = 4.4, J = 1.6, H-8). 13C NMR spectrum, , ppm: 116.5 (CH); 121.2
4
3
4
995

(CH); 122.0 (CH); 124.7 (CH); 126.7 (C); 128.4 (C); 128.6 (C); 131.4 (CH); 132.1 (CH); 135.6 (C); 136.5
(CH); 137.3 (C); 150.7 (CH); 151.4 (C); 153.5 (C); 182.4 (C=O). Mass spectrum (79Br isotope), m/z (Irel, %):
351 [M]+ (83), 323 [M-CO]+ (7), 272 [M-Br]+ (26), 244 [M-Br-CO]+ (10), 216 (14), 196 [M-C6H4Br]+ (100),
183 [BrC6H4CO]+ (42), 155 [BrC6H4]+ (43), 140 (84). Found, %: С 61.44; Н 2.92; N 4.02. C18H10BrNO2.
Calculated, %: C 61.39; H 2.86; N 3.98.
This work was carried out with the financial support of the Grant Council of the President of Russian
Federation (grant MK-3368.2011.3) and the Ministry of Education and Science of the Russian Federation
(contract 16.5552.11.7016 from 29.04.2011) with the use of the scientific equipment of the Collective Use
Center "Investigation of the physicochemical properties of substances and materials".
REFERENCES
1.
2.
3.
4.
5.
R. C. Schnur, US Pat. Appl. 4176185.
P. A. Cruickshank, F. T. Lee, and A. Lupichuk, J. Med. Chem., 13, 1110 (1970).
A. Arrault, G. Guillaumet, J.-M. Leger, C. Jarry, and J.-Y. Merour, Synthesis, 1879 (2002).
I. Yavari and Z. Hossaini, Tetrahedron Lett., 46, 4465 (2006).
H. Meinhold, M. Muhlstadt, and R. M. Muslih, J. Prakt. Chem., 331, 136 (1989).
H. Togo and O. Kikuchi, Heterocycles, 28, 373 (1989).
6.
7.
H. Timmler and H. Andersag, DE Pat. Appl. 937588.
8.
9.
10.
11.
12.
S. Malik, U. K. Nadir, and P. S. Pandey, Tetrahedron, 65, 3918 (2009).
Y. Han, H. Hou, R. Yao, Q. Fu, and C.-G. Yan, Synthesis, 4061 (2010).
C.-P. Chuang and A.-I. Tsai, Synthesis, 675 (2006).
V. A. Osyanin, E. A. Ivleva, and Y. N. Klimochkin, Synth. Commun., 42, 1832 (2012).
V. A. Osyanin, D. V. Osipov, and Yu. N. Klimochkin, Khim. Geterotsikl. Soedin., 469 (2010). [Chem.
Heterocycl. Compd., 46, 377 (2010)].
13.
14.
15.
16.
17.
Q.-F. Wang, X.-K. Song, J. Chen, and C.-G. Yan, J. Comb. Chem., 11, 1007 (2009).
C. G. Stuckwisch, Synthesis, 469 (1973).
J. H. Burckhalter and R. I. Leib, J. Org. Chem., 26, 4078 (1961).
F. Krohnke, Chem. Ber., 69, 921 (1936).
K. Ohga, Y. Takashima, H. Takahashi, Y. Kawaguchi, H. Yamaguchi, and A. Harada, Macromolecules
(Washington, DC, U. S.), 38, 5897 (2005).
18.
19.
Y.-M. Shen, P.-C. Lv, W. Chen, P.-G. Liu, M.-Z. Zhang, and H.-L. Zhu, Eur. J. Med. Chem., 45, 3184
(2010).
W. G. Phillips and K. W. Ratts, J. Org. Chem., 35, 3144 (1970).
996