6,6-Heptamethylenetetrahydropyran-2,4-dione in the synthesis of benzo[f]pyrano[3,4-b]quinolines and pyrano[4,3-b][4,7]phenanthrolines

Article abstract of DOI:10.1023/B:RUJO.0000036079.00169.3b

Three-component condensation of 6,6-heptamethylenetetrahydropyran-2,4-dione with 2-amino-naphthalene or 6-aminoquinoline and aromatic aldehydes in an aliphatic alcohol afforded 12-aryl-9,9-hepta-methylene-8,9,10,12-tetrahydro-7H- benzo[f]pyrano[3,4-b]quinolin-11-ones and 12-aryl-9,9-heptamethylene-8,9,10,12- tetrahydro-7H-pyrano[4,3-b][4,7]phenanthrolin-11-ones, new N,O-heterocycles which include azaor diazaphenanthrene system fused to α-pyrone ring and aromatic and spiro substituents.

Full text of DOI:10.1023/B:RUJO.0000036079.00169.3b

Russian Journal of Organic Chemistry, Vol. 40, No. 4, 2004, pp. 555–559. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 4, 2004,
pp. 584–588.
Original Russian Text Copyright © 2004 by Kozlov, Pashkovskii, Gusak, Koroleva, Tereshko, Lokot’.
6,6-Heptamethylenetetrahydropyran-2,4-dione
in the Synthesis of Benzo[f]pyrano[3,4-b]quinolines
and Pyrano[4,3-b][4,7]phenanthrolines
N. G. Kozlov, F. S. Pashkovskii, K. N. Gusak, E. V. Koroleva,
A. B. Tereshko, and I. P. Lokot’
Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus,
ul. Surganova 13, Minsk, 220072 Belarus
e-mail: loc@ifoch.bas-net.by
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus,
ul. Akademika Kuprevicha 5/2, Minsk, 220141 Belarus
e-mail: prostan@iboch.bas-net.by
Received April 24, 2003
Abstract—Three-component condensation of 6,6-heptamethylenetetrahydropyran-2,4-dione with 2-amino-
naphthalene or 6-aminoquinoline and aromatic aldehydes in an aliphatic alcohol afforded 12-aryl-9,9-hepta-
methylene-8,9,10,12-tetrahydro-7H-benzo[f]pyrano[3,4-b]quinolin-11-ones and 12-aryl-9,9-heptamethylene-
8,9,10,12-tetrahydro-7H-pyrano[4,3-b][4,7]phenanthrolin-11-ones, new N,O-heterocycles which include aza-
or diazaphenanthrene system fused to α-pyrone ring and aromatic and spiro substituents.
High and versatile biological activity of benzo[f]-
quinoline and 4,7-phenanthroline derivatives [1–6]
makes it promising to search for new synthons en-
suring preparation of previously unknown derivatives
of the above series. We showed in [7–9] that cyclic
β-diketones are highly effective reagents in the syn-
thesis of fused benzo[f]quinoline and 4,7-phenanthro-
line derivatives.
boiling ethanol or 1-butanol in the absence of
a catalyst. As a result, we isolated pure benzo[f]-
pyrano[3,4-b]quinoline (IVa, IVb) and pyrano[4,3-b]-
[4,7]phenanthroline (IVc–IVe) derivatives in 67–87%
yield (Scheme 1).
Theoretically, the three-component condensation of
ketolactone I, amine II, and aldehyde III can take
several pathways to give different isomeric products.
Analogous reactions with cyclic ketones are known to
involve intermediate formation of Schiff bases from
the corresponding amine and aldehyde, and the sub-
sequent condensation with cycloalkanone yields aza-
phenanthrene derivatives [11, 12] following the well-
known mechanism for reactions of CH acids with
Schiff bases [1]. In this case, the condensation of
ketolactone I with 2-aminonaphthalene (IIa) or
6-aminoquinoline (IIb) and benzaldehyde III could
lead to formation of benzo[f]pyrano[3,4-c]quinoline
or pyrano[3,4-a][4,7]phenanthroline derivatives like A.
However, the formation of benzo[f]pirano[3,4-b]quino-
lines and pyrano[4,3-b][4,7]phenanthrolines IV in-
dicates that the condensation takes a different pathway.
We believe that in the initial stage spirocyclic pyran-
dione I reacts with amine II or aldehyde III to give,
respectively, enamine B or enol C. Reactions of
With the goal of introducing a fused oxygen-con-
taining ring and a spiro-fused cycloalkane ring into the
nitrogen heterocycle molecule, in the present work we
were the first to examine the reaction of 6,6-hepta-
methylenetetrahydropyran-2,4-dione (I) with 2-amino-
naphthalene (IIa) or 6-aminoquinoline (IIb) and sub-
stituted benzaldehydes IIIa–IIIe. Spirocyclic pyrandi-
one I was synthesized by the procedure developed by
us previously [10]; it may be regarded as a hetero-
cyclic analog of substituted 1,3-cyclohexanedione.
However, unlike the latter, the ketone and lactone
carbonyl groups in the enolizable β-dicarbonyl frag-
ment of molecule I are chemically nonequivalent.
The condensation of pyrandione I with amines IIa
and IIb and benzaldehydes IIIa–IIIe were carried out
by heating equimolar amounts of the reactants in
1070-4280/04/4004-0555 © 2004 MAIK “Nauka/Interperiodica”

KOZLOV et al.
556
Scheme 1.
O
O
CHO
NH2
O
+
+
R
X
I
IIa, IIb
IIIa–IIIe
R
O O
O
O
O
O
O
O
O
HO
OH
OH
NH
N
X
X
R
R
V
C
B
R
O O
O
O
O
O
O
O
R
HO
NH
OH
HN
NH
X
X
X
R
E
D
A
10
O
O
11
9
8
R
11a
12
7a
1
7NH
6a
12a
12b
4a
2
3
6
4
X
5
IVa–IVe
IIa, IVa, IVb, X = CH; IIb, IVc–IVe, X = N; III, IV, R = 4-OH (a), 4-Cl (b), 4-Br (c), 2,4-(MeO)2 (d), 3,4-(MeO)2 (e); V, R = 4-Br.
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6,6-HEPTAMETHYLENETETRAHYDROPYRAN-2,4-DIONE IN THE SYNTHESIS
557
intermediates B and C with the third component (III or
II) yields the same intermediate enaminoketone D, and
dehydration of the latter results in formation of final
products IVa–IVe (Scheme 1). Analogous products,
benzo[f]quinoline derivatives, were obtained pre-
viously by reaction of 2-aminonaphthalene with
dimedone (which is a carbocyclic analog of pyran-
dione I) and aromatic aldehydes [13].
(1580, 1520 cm–1) [13]. A considerable shift of the
first of these bands toward higher frequencies may be
due to lactone nature of the carbonyl group. Strong
bands at 3280 and 1640 cm–1 belong, respectively, to
stretching and bending vibrations of the secondary
amino group.
In the mass spectra of benzopyranoquinolines and
pyrano-4,7-phenanthrolines IVa–IVe we observed the
molecular ion peaks [M]+ (Irel 10–30%), while the most
abundant ion was [M – C6H4R]+ (100%) (or [M –
C6H3R]+ for dimethoxyphenyl-substituted compounds
IVd and IVe), m/z 346 (IVa, IVb), 347 (IVc–IVe). The
mass spectra of phenanthrolines IVd and IVe con-
tained an ion peak with m/z 374, Irel 55% (IVd) and
18% (IVe). The presence of that ion indicates con-
current elimination of the spirocyclooctane fragment
C8H14 from the molecular ion. Fairly abundant (Irel 28–
50%) ions with m/z 220 for benzoquinolines IVa and
IVb and m/z 221 for phenanthrolines IVc–IVe result
from successive elimination of the C6H4(3)R and
C8H14O fragments from the molecular ion, and ions
with m/z 192 (IVa, IVb) and 193 (IVc–IVe) (Irel 34–
53%) correspond to the subsequent elimination of
carbonyl group from ion with m/z 220 (221). The
fragment ion [M – C6H4(3)R]+ derived from IVa, IVd,
and IVe is stabilized by addition of hydrogen to give,
respectively, phenol (m/z 94, Irel 10%) and m- and
o-dimethoxybenzene (m/z 138, Irel 34–50%). The
observed fragmentation pattern confirms the assumed
structure of compounds IVa–IVe; specifically, the
presence of an ion peak with m/z 192 (193) indicates
that the polycyclic molecule contains a lactone car-
bonyl group. Just in this case the methylene group
of the pyran ring, which is directly attached to the
aza(diaza)phenanthrene skeleton, is included in the
above ion.
In the reaction with p-bromobenzaldehyde (IIIc),
apart from the major product, 4,7-phenanthroline IVc,
we isolated a small amount of p-bromophenyl-
methylene-3,3'-bis(6,6-heptamethylene-4-hydroxy-5,6-
dihydro-2H-pyran-2-one) (V). Compound V was also
synthesized in a preparative yield by reaction of pyran-
dione I with aldehyde IIIc under the above condensa-
tion conditions; by heating with 6-aminoquinoline
(IIb), bis-ketone V was converted into pyranophenan-
throline IVc. Obviously, elimination of pyrandione
molecule from intermediate E gives enaminoketone D
whose dehydration leads to compound IVc. Taking
into account that the lactone carbonyl group in I is
less prone to enolization, as compared to the ketone
carbonyl [14, 15], these reactions involve just the
ketone carbonyl group. As a result, the lactone car-
bonyl group is retained in the structure of polycyclic
compounds IVa–IVe.
The structure of compounds IVa–IVe was proved
by NMR, IR, and UV spectroscopy and mass spec-
1
trometry. The H NMR spectra of IVa–IVe resemble
those of the previously reported fused benzo[f]quino-
line and 4,7-phenanthroline derivatives, as concerns
the positions and multiplicities of signals belonging to
the benzopyranoquinoline and pyranophenanthroline
fragments [8, 9, 11, 12]. The spiro-fused cyclooctane
ring gives rise to a 14-proton multiplet in the δ region
from 1.30 to 2.05 ppm. The R substituent almost does
not affect the chemical shifts of protons of the aza-
phenanthrene moiety; only in the spectrum of 2,4-di-
methoxyphenyl-substituted 4,7-phenanthroline IVd we
observed a downfield shift of the 1-H proton signal,
in keeping with the assumed structure. Presumably,
the presence of a bulky methoxy group in the ortho
position of the phenyl ring changes spatial arrange-
ment of the latter, so that its shielding effect on the
1-H proton of the phenanthroline fragment weakens.
No such pattern would be observed for alternative
struc-ture A where the 1-H proton is distant from the
aryl substituent.
The electron absorption spectra of spirocyclic
benzopyranoquinoline and 4,7-phenanthroline deriva-
tives IVa–IVe occupy the ultraviolet region and are
characterized by clearly defined vibrational structure.
Molecules IVa–IVe possess three independent
chromophores: naphthalene (quinoline) fragment, aryl
substituent, and carbonyl group. Insofar as the naph-
thalene (quinoline) core contributes most to π–π*-elec-
tron transitions, the first three bands in the spectra of
IVa–IVe may be attributed to the 2-aminonaphthalene
(6-aminoquinoline) system, λmax, nm (logε): 206–208
(4.08–4.11), 247–249 (4.35–4.39), 279–283 (3.59–
3.64). An appreciable red shift and increase in the
intensity of the first and third bands in the spectra of
pyrano derivatives IVa–IVe are likely to result from
The IR spectra of compounds IVa–IVe contain
strong absorption bands at 1665 and 1525 cm–1, which
should be assigned to the enaminoketone fragment
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 4 2004

KOZLOV et al.
558
superposition of absorption bands belonging to the
aromatic C6H4(3)R substituent. Absorption bands in the
short-wave region arise from the presence of a car-
bonyl group [16].
7.70–7.92 m (10H, 1-H–6-H, C6H4), 9.80 s (1H, NH).
UV spectrum, λmax, nm (logε): 213 (4.59), 223 (4.71),
274 (4.20), 289 (4.28), 336 (3.94), 371 (3.90). Found,
%: C 75.89; H 5.94; Cl 7.53; N 3.18. C29H28ClNO2.
Calculated, %: C 76.07; H 6.12; Cl 7.76; N 3.06.
Thus we have shown that three-component con-
densation of 6,6-heptamethylenetetrahydropyran-2,4-
dione, 2-aminonaphthalene or 6-aminoquinoline, and
aromatic aldehyde provides a convenient one-step
procedure for the synthesis of difficultly accessible
fused N,O-heterocycles containing aza(diaza)phenan-
threne and pyran nuclei, spiro-fused cyclooctane ring,
and aryl substituent.
12-Aryl-9,9-heptamethylne-8,9,10,12-tetrahydro-
7H-pyrano[4,3-b][4,7]phenanthrolin-11-ones IVc–
IVe were synthesized in a similar way from pyran-
dione I, 6-aminoquinoline (IIb) and aldehyde IIIc–
IIIe by heating in boiling 1-butanol for 2 h. Products
IVc–IVe were recrystallized from ethanol–benzene
(2:1) without preliminary treatment with boiling
benzene.
EXPERIMENTAL
12-(4-Bromophenyl)-9,9-heptamethylene-8,9,-
10,12-tetrahydro-7H-pyrano[4,3-b][4,7]phenanthro-
lin-11-one (IVc). Yield 67%, mp 299–300°C. 1H NMR
spectrum, δ, ppm (J, Hz): 1.30–2.07 m (14H, CH2),
2.60 s (1H, 8-H), 5.70 s (1H, 12-H), 7.16 d and 7.25 d
The mass spectra (70 eV) were recorded on a Finni-
gan MAT Incos-50 instrument. The IR spectra were
measured on a Nicolet Protégé 460 Fourier spectrom-
1
eter. The H NMR spectra were obtained on a Tesla
3
3
4
(6H, C6H4, J = 7.8), 7.28 d.d (1H, 2-H, J = 8.2, J =
BS-567 instrument (100 MHz) in DMSO-d6 (IVa–IVe)
or CDCl3 (V) using TMS as internal reference. The
UV spectra were measured from solutions in ethanol
(c = 10–4 M) on a Specord UV-Vis spectrophotometer.
The melting points were determined on a Koeffler
device.
2.8), 7.41 d and 7.83 d (2H, 5-H, 6-H, 3J = 8.4), 8.16 d
3
3
(1H, 1-H, J = 4.2), 8.60 d (1H, 3-H, J = 4.6), 9.51 s
(1H, NH). UV spectrum, λmax, nm (logε): 219 (4.60),
255 (4.20), 291 (4.18), 332 (4.00), 376 (3.89). Found,
%: C 66.51; H 5.28; Br 15.94; N 5.33. C28H27BrN2O2.
Calculated, %: C 66.80; H 5.37; Br 15.90; N 5.57.
6,6-Heptamethylenetetrahydropyran-2,4-dione (I)
9,9-Heptamethylene-12-(2,4-dimethoxyphenyl)-
8,9,10,12-tetrahydro-7H-pyrano[4,3-b][4,7]phenan-
throlin-11-one (IVd). Yield 87%, mp 258–260°C.
1H NMR spectrum, δ, ppm (J, Hz): 1.42–2.05 m (14H,
C8H14); 2.61 s (1H, 8-H); 3.70 s and 3.92 s (6H,
2OMe); 5.90 s (1H, 12-H); 6.37 s, 6.28 d, and 7.09 d
was synthesized by the procedure described in [10].
12-Aryl-9,9-heptamethylene-8,9,10,12-tetra-
hydro-7H-benzo[f]pyrano[3,4-b]quinolin-11-ones
IVa and IVb. A mixture of 5 mmol of pyrandione I,
5 mmol of 2-aminonaphthalene (IIa), and 5 mmol of
aldehyde IIIa or IIIb in 20 ml of ethanol was heated
for 1 h under reflux. The precipitate was filtered off,
treated with boiling benzene to remove unreacted
initial compounds, and dried.
3
3
4
(3H, C6H3, J = 7.6); 7.27 d.d (1H, 2-H, J = 8.2, J =
2.8); 7.36 d and 7.74 d (2H, 5-H, 6-H, 3J = 8.4), 8.51 d
3
3
(1H, 1-H, J = 4.2), 8.58 d (1H, 3-H, J = 4.6), 9.37 s
(1H, NH). UV spectrum, λmax, nm (logε): 216 (4.62),
256 (4.22), 293 (4.19), 330 (3.99), 373 (3.91). Found,
%: C 74.08; H 6.49; N 5.63. C30H32N2O4. Calculated,
%: C 74.38; H 6.61; N 5.79.
9,9-Heptamethylene-12-(4-hydroxyphenyl)-
8,9,10,12-tetrahydro-7H-benzo[f]pyrano[3,4-b]-
quinolin-11-one (IVa). Yield 77%, mp 324–325°C. 1H
NMR spectrum, δ, ppm (J, Hz): 1.20–2.03 m (14H,
CH2), 2.58 s (1H, 8-H), 5.57 s (1H, 12-H), 6.51 d and
9,9-Heptamethylene-12-(2,4-dimethoxyphenyl)-
8,9,10,12-tetrahydro-7H-pyrano[4,3-b][4,7]phenan-
throlin-11-one (IVe). Yield 79%, mp 252–253°C.
1H NMR spectrum, δ, ppm (J, Hz): 1.35–2.00 m (14H,
C8H14); 2.60 s (1H, 8-H); 3.68 s and 3.72 s (6H,
2OMe); 5.63 s (1H, 12-H); 6.53 d, 6.61 d, and 6.90 s
3
6.98 d (4H, C6H4, J = 7.5), 7.12–7.45 m and 7.58–
7.80 m (6H, 1-H–6-H), 8.00 s (1H, OH), 9.38 s (1H,
NH). UV spectrum, λmax, nm (logε): 217 (4.63), 227
(4.73), 277 (4.21), 288 (4.31), 334 (3.98), 368 (3.94).
Found, %: C 79.11; H 6.43; N 3.22. C29H29NO3. Cal-
culated, %: C 79.27; H 6.61; N 3.19.
3
4
(3H, C6H3, J = 7.5); 7.29 d.d (3J = 8.2, J = 2.8);
7.42 d and 7.82 d (3J = 8.4); 8.23 d (3J = 4.2); 8.61 d
(3J = 4.6); 9.42 s (1H, NH). UV spectrum, λmax, nm
(logε): 213 (4.61), 252 (4.19), 290 (4.17), 333 (4.01),
374 (3.96). Found, %: C 74.24; H 6.52; N 5.39.
C30H32N2O4. Calculated, %: C 74.38; H 6.61; N 5.79.
12-(4-Chlorophenyl)-9,9-heptamethylene-8,9,-
10,12-tetrahydro-7H-benzo[f]pyrano[3,4-b]quino-
lin-11-one (IVb). Yield 68%, mp 285–286°C. H
1
NMR spectrum, δ, ppm: 1.30–1.90 m (14H, C8H14),
2.59 s (1H, 8-H), 5.71 s (1H, 12-H), 7.20–7.50 m and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 4 2004

6,6-HEPTAMETHYLENETETRAHYDROPYRAN-2,4-DIONE IN THE SYNTHESIS
559
2. Bahner, S.T. and Kinder, H., J. Med. Chem., 1965,
3,3'-p-Bromophenylmethylenebis(6,6-hepta-
methylene-4-hydroxy-5,6-dihydropyran-2-one) (V)
was synthesized from dione I, amine IIb, and aldehyde
IIIc, following the procedure described above for
compounds IVa–IVc. After separation of the major
product (phenanthroline IVc), the mother liquor was
evaporated, and the residue was recrystallized from
ethanol–benzene (4:1). Yield 8%, mp 205–206°C.
IR spectrum, ν, cm–1: 1655 (C=O), 2960–2880 (CH2).
1H NMR spectrum, δ, ppm: 1.40–2.35m (28H, CH2),
2.60 s (4H, CH2), 5.30 s (1H, CH), 6.88 d and 7.32 d
(4H, Harom), 11.3 br.s (2H, OH). Found, %: C 62.54;
H 6.47; Br 13.73. C30H38BrO6. Calculated, %: C 62.72;
H 6.62; Br 13.94.
vol. 8, p. 1378.
3. Cannon, J.G., Suarez-Gutierrez, C., Lee, T., Long, J.P.,
Costall, B., Fortune, D.H., and Naylor, R.J., J. Med.
Chem., 1979, vol. 22, p. 341.
4. EVP Patent no. 13666, 1980; Chem. Abstr., 1981,
vol. 94, no. 15704x.
5. Bicsak, T.A., Rann, L.R., Reiter, A., and Chase, T.,
Arch. Biochem. Biophys., 1982, vol. 216, p. 605.
6. Husseini, R. and Stretton, R.J., Microbios, 1981, vol. 30,
p. 7.
7. Lielbriedis, I.E. and Gudrinietse, E.V., Izv. Akad. Nauk
Latv. SSR, Ser. Khim., 1969, no. 2, p. 193.
8. Kozlov, N.S., Gusak, K.N., and Bezborodov, V.S., Russ.
J. Org. Chem., 2000, vol. 36, p. 88.
Bis-ketone V was also synthesized by heating
a mixture of 10 mmol of pyrandione I and 5 mmol of
aldehyde IIIc in 20 ml of ethanol for 1.5 h under
reflux. Yield 86%.
9. Kozlov, N.S. and Gusak, K.N., Dokl. Akad. Nauk SSSR,
1990, vol. 314, p. 1419.
10. Lokot’, I.P., Pashkovskii, F.S., and Lakhvich, F.A.,
Khim. Geterotsikl. Soedin., 2001, p. 768.
Condensation of 3,3'-p-bromophenylmethylene-
bis(6,6-heptamethylene-4-hydroxy-5,6-dihydro-
pyran-2-one) (V) with 6-aminoquinoline (IIb). A so-
lution of 5 mmol of compound V and 5 mmol of amine
IIb in 20 ml of 1-butanol was heated for 1 h. The
product (compound IVc) was isolated as described
above. Yield 76%.
11. Kozlov, N.G., Popova, L.A., and Yakubovich, L.S.,
Russ. J. Org. Chem., 2000, vol. 36, p. 1667.
12. Kozlov, N.G. and Basalaeva, L.I., Russ. J. Gen. Chem.,
2001, vol. 71, p. 250.
13. Martinez, R., Cortes, E., and Toscano, R.A., J. Hetero-
cycl. Chem., 1990, vol. 27, p. 363.
14. Berson, J.A., J. Am. Chem. Soc., 1952, vol. 74, p. 5172.
15. Berson, J.A., Jones, W.M., and O’Callagen, S.L.F.,
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 4 2004