Fused polycyclic nitrogen-containing heterocycles 24.* Three-component condensation of diethyl 2, 4, 6-trioxoheptanedicarboxylate with salicylaldehydes and ammonium acetate as a new method for the synthesis of 7-and 9-substituted benzo[e]pyrano[4, 3-b]pyr

Article abstract of DOI:10.1007/s11172-009-0195-z

The three-component condensation of diethyl 2, 4, 6- trioxoheptanedicarboxylate with salicylaldehyde and its 3, 5-dichloro-, 3-methoxy-, and 5-methoxy-substituted derivatives in EtOH in the presence of ammonium acetate affords tricyclic products, viz., te

Full text of DOI:10.1007/s11172-009-0195-z

Russian Chemical Bulletin, International Edition, Vol. 58, No. 7, pp. 1452—1464, July, 2009
1452
Fused polycyclic nitrogenꢀcontaining heterocycles
24.* Threeꢀcomponent condensation of diethyl 2,4,6ꢀtrioxoheptanedicarboxylate
with salicylaldehydes and ammonium acetate as a new method for the synthesis
of 7ꢀ and 9ꢀsubstituted benzo[e]pyrano[4,3ꢀb]pyridines
V. A. Mamedov, L. P. Sysoeva, A. M. Murtazina, E. A. Berdnikov, A. T. Gubaidullin,
S. F. Kadyrova, E. V. Mironova, and I. A. Litvinov
A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Research Center of the Russian Academy of Sciences,
8 ul. Akad. Arbuzova, 420088 Kazan, Russian Federation.
Fax: +7 (843) 273 2253. Eꢀmail: mamedov@iopc.knc.ru
The threeꢀcomponent condensation of diethyl 2,4,6ꢀtrioxoheptanedicarboxylate with saliꢀ
cylaldehyde and its 3,5ꢀdichloroꢀ, 3ꢀmethoxyꢀ, and 5ꢀmethoxyꢀsubstituted derivatives in EtOH
in the presence of ammonium acetate affords tricyclic products, viz., tetrahydrobenzo[e]ꢀ
pyrano[4,3ꢀb]pyridines. In the reaction with 3ꢀnitrosalicylaldehyde, the intramolecular closure
of the pyran ring does not occur due to the deactivation of the hydroxy group by the nitro group,
and this reaction stops at the formation of the monocyclic product, viz., tetrahydropyridinꢀ4ꢀone.
Key words: diethyl 2,4,6ꢀtrioxoheptanedicarboxylate, salicylaldehyde, threeꢀcomponent
condensation, benzopyrano[4,3ꢀb]pyridine, IR spectroscopy, NMR spectroscopy, Xꢀray difꢀ
fraction study.
Tetrahydrobenzo[e]pyrano[4,3ꢀb]pyridines2—19 (or pyꢀ
Scheme 1
rido[3,2ꢀc]coumarines20) are aza analogs of Δ1ꢀtransꢀtetꢀ
rahydrocannabinol (1)21 and Δ1(6)ꢀtransꢀtetrahydrocanꢀ
nabinol (2),22 which are known physiologically active
components of Cannabis.23 In this context, a search for
new methods for the synthesis of this interesting tricyclic
system has attracted considerable attention.2—20
Previously,24 we have found that the reaction of diꢀ
ethyl 2,4,6ꢀtrioxoheptanedicarboxylate (3) (hereinafter,
diethoxalylacetone) with salicylaldehyde (4a) in EtOH in
the presence of ammonium acetate produces the aza anaꢀ
log of the heterocyclic cannabinol system, viz., 2,5ꢀdiꢀ
ethoxycarbonylꢀ5ꢀhydroxyꢀ4ꢀoxoꢀ1,4,4a,10bꢀtetrahydroꢀ
benzo[e]pyrano[4,3ꢀb]pyridine (5a) (Scheme 1).
5.00 (J = 16.2 Hz), which are indicative of the presꢀ
ence of protons of the AX system in the mutual trans
arrangement. It should be noted that the signals for proꢀ
tons in the spectrum of the crude product are doubled,
which is evidence for the formation of two diastereomers.
The integrated intensity ratio for the signals of these diaꢀ
stereomers is 1 : 10. We failed to isolate the diastereomer,
The 1H NMR spectrum of the reaction product,
which was isolated in the pure form in 70% yield, shows,
along with other signals, two doublets at δ 3.27 and
* For Part 23, see Ref. 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1410—1421, July, 2009.
1066ꢀ5285/09/5807ꢀ1452 © 2009 Springer Science+Business Media, Inc.

Tetrahydrobenzo[e]pyrano[4,3ꢀb]pyridines
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
1453
Scheme 2
which was present in the mixture in an amount of ~9%, in
the pure form.
tetrahydrobenzo[e]pyrano[4,3ꢀb]pyridine 5 suggests that
the latter compound can exist in different forms, includꢀ
ing openꢀchain structures, depending on the phase state
and the polarity of the medium (Scheme 2).
The Xꢀray diffraction study showed24 that the asymꢀ
metric carbon atoms in compound 5a have the relative
configuration C(4a)S,C(5)R,C(10b)R (Fig. 1).
Since both steps of the pyridꢀ4ꢀone and pyran ring
closure in the reaction giving tetrahydrobenzo[e]pyranoꢀ
[4,3ꢀb]pyridine 5a are reversible25,26 and lead to the forꢀ
mation of three asymmetric centers, compound 5 can exꢀ
ist as eight isomers, which can potentially be isolated as
four diastereomeric pairs.
The nature of the substituents in substituted salicylꢀ
aldehyde can influence the tautomeric equilibrium from
the very beginning of the formation of the tricyclic system,
thus determining the formation of a particular tautomer
and, consequently, of the diastereomer. In this context, in
the present study we made efforts to elucidate the influꢀ
ence of the nature of the substituents in salicylaldehydes
on the structure of the final products and the pathways of
their formation in the threeꢀcomponent condensation unꢀ
der consideration (Scheme 3).
The presence of two systems capable of forming tauꢀ
tomers (2ꢀhydroxypyran and tetrahydropyridinꢀ4ꢀone) in
C(14)
Scheme 3
C(13)
O(11)
O(12)
C(11)
N(1)
C(2)
C(3)
O(4)
C(4a)
C(10b)
C(9)
C(8)
C(4)
O(16)
C(18)
C(10)
C(10a)
C(5)
C(17)
C(6a)
C(7)
O(6)
O(5)
O(15)
C(15)
4, 5: R1 = R2 = H (a); R1 = R2 = Cl (b);
R
1 = OMe, R2 = H (c); R1 = H, R2 = OMe (d)
The reactions of diethoxalylacetone 3 (see Ref. 24)
with 3,5ꢀdichloroꢀ, 3ꢀmethoxyꢀ, and 5ꢀmethoxysalicylꢀ
aldehydes 4b—d, respectively, in EtOH in the presence of
ammonium acetate give products 5b—d with a tricyclic
Fig. 1. Molecular structure of 5a in the crystal.

1454
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
Mamedov et al.
structure in good yields. An analysis of the 1H NMR specꢀ
tra of the crude products showed that all reactions afford
mixtures of diastereomers. Thus, the signals for protons in
the same group at the C(5) atom differ by 0.02 ppm, which
is apparently associated with the fact that the former proꢀ
tons are more distant from the asymmetric centers.
The reactions of 3ꢀ and 5ꢀmethoxyꢀsubstituted salicyꢀ
laldehydes give diastereomeric mixtures of compounds 5c
and 5d with the cis (J = 6.5 Hz and J = 6.6 Hz) and trans
arrangement (J = 15.8 Hz and J = 16.1 Hz) of the bridgeꢀ
head hydrogen atoms of the tricyclic systems, respectiveꢀ
ly. The ratio of the diastereomers of tricyclic compound
5c in the mixture is ~1 : 2, whereas the corresponding ratio
for tricyclic compound 5d is 2 : 1. The nonequivalence of
the methylene protons of the ethoxycarbonyl group at the
C(5) atom in tricyclic systems 5c,d is manifested in the
1H NMR spectra as the 0.18 ppm difference between the
chemical shifts. This difference is approximately equal for
both systems.
According to the Xꢀray diffraction data, the asymmetric
carbon atoms in the diastereomer isolated from the reacꢀ
tion with 3ꢀmethoxysalicylaldehyde (4c) have the relative
configuration C(4a)S,C(5)R,C(10b)R (Fig. 3), whereas the
asymmetric carbon atoms in the diastereomer isolated from
the reaction with 5ꢀmethoxysalicylaldehyde (4d) have the
configuration C(4a)R,C(5)R,C(10b)R (Fig. 4).
1
the H NMR spectrum of the product prepared with the
use of 3,5ꢀdichlorosalicylaldehyde (4b) are doubled, which
is indicative of the formation of two diastereomers; the
integrated intensity ratio is 1 : 5. For the major diastereoꢀ
mer, the bridgehead protons H(4a) and H(10b) resonate
at δ 3.58 and 5.02 (J = 7.4 Hz), respectively; for the minor
diastereomer, the signals for the bridgehead protons are
observed at δ 3.12 and 4.86 (J = 15.8 Hz). These diagnosꢀ
tic signals provide evidence for the formation of the tricyꢀ
clic systems containing bridgehead protons in different
orientations rather than for the formation of only the pyriꢀ
dinꢀ4ꢀone or benzopyran systems. The Xꢀray diffraction
data confirmed the cis orientations of the protons H(4a)
and H(10b) in the major product of the reaction occurring
with the participation of 3,5ꢀdichlorosalicylaldehyde, the
asymmetric carbon atoms of this compound having the
relative configuration C(4a)R,C(5)R,C(10b)R (Fig. 2). It
should also be noted that the nonequivalence of the diasꢀ
tereomeric methylene protons of two ethoxycarbonyl fragꢀ
ments of compound 5b is manifested in the 1H NMR
spectrum in different ways. The signals for the methylene
protons of the ethoxycarbonyl group at the C(2) atom
coincide, whereas the signals for the methylene protons of
The crystal and molecular structures of compounds
5a,c,d (see Figs 1, 3, and 4, respectively) have been deꢀ
scribed in detail previously.27 In the present study, we
C(13)
C(14)
C(14)
C(13)
O(11)
O(11)
O(12)
O(12)
C(11)
C(11)
C(2)
N(1)
C(2)
Cl(2)
C(3)
N(1)
C(10)
C(10a)
C(10)
C(3)
C(4)
C(10b)
C(4)
C(10b)
C(9)
C(9)
O(4)
O(4)
C(10a)
O(6)
C(4a)
O(16)
C(5)
C(4a)
C(5)
C(15)
C(6a)
O(6)
C(7)
C(8)
C(7)
C(18)
C(8)
O(16)
C(6a)
O(7)
C(18)
C(17)
O(5)
O(5)
C(15) C(17)
O(15)
Cl(1)
C(19)
O(15)
Fig. 2. Molecular structure of 5b in the crystal.
Fig. 3. Molecular structure of 5c in the crystal.

Tetrahydrobenzo[e]pyrano[4,3ꢀb]pyridines
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
1455
those in molecules 5a,c, is in an eclipsed conformation
(the C(3)—C(2)—C(11)—O(12) torsion angle is 8.8(3)°).
This conformation of the substituent is stabilized by the
intramolecular N(1)—H(1)...O(11) hydrogen bond (the
hydrogen bond parameters are given in Table 2).
The pyran ring in molecule 5b, like these rings in molꢀ
ecules 5a,c,d, adopts a halfꢀchair conformation. The
O(6)C(6a)C(10a)C(10b) fragment is planar within
0.006(2) Å. The C(4a) and C(5) atoms deviate from this
plane by 0.585(2) and –0.167(2) Å, respectively. The tetꢀ
rahydropyridine ring in molecule 5b adopts a Cꢀenvelop
conformation, in which the C(10b)N(1)C(2)C(3)C(4)
fragment is planar within 0.110(2) Å and the C(4a) atom
deviates from this plane by 0.551(2) Å, whereas the tetraꢀ
hydropyridine ring in molecules 5a,c,d has a halfꢀchair
conformation.
C(13)
C(14)
O(11)
C(11)
O(12)
C(2)
C(3)
C(4)
N(1)
C(19)
C(10b)
C(10)
O(4)
C(9)
C(8)
C(4a)
C(5)
O(16)
C(10a)
O(6)
O(9)
C(17)
C(18)
C(6a)
C(15)
C(7)
O(5)
O(15)
In the crystal structure of compound 5b, the molecules
are linked to each other by classical hydrogen bonds to
form a 1D structure, similar to those observed in the crysꢀ
tals of compounds 5a,c,d (the hydrogen bond parameters
are given in Table 2). Thus, the dimers of the molecules
formed through the O(5)—H(5)...O(15) hydrogen bond
are linked to each other by the N(1)—H(1)...O(4) hydroꢀ
gen bonds to form chains running along the 0a axis of the
crystal (Fig. 5). In the crystal structure of compound 5b,
a layered structure is formed through C—H...O and
C—H...Cl interactions. The layers are parallel to the a0b
plane of the crystal.
The Xꢀray diffraction study of compounds 5a—d
showed that all these compounds are tricyclic isomers.
Therefore, the threeꢀcomponent condensation of salꢀ
icylaldehydes containing electronꢀdonating substituꢀ
ents affords a tricyclic system. It should be noted that the
formation of the pyran ring occurs strictly diastereoseꢀ
lective. Thus, the diastereomers (10bR,4aS,5S)ꢀ5a and
Fig. 4. Molecular structure of 5d in the crystal.
analyzed the structure of compound 5b; the structures of
compounds 5a,c,d were used for the comparison.
Compound 5b (see Fig. 2) crystallizes as a racemate
with the chiral centers having the relative configuration
C(4a)R,C(5)R,C(10b)R (or C(4a)S,C(5)S,C(10b)S in the
molecule related to the reference molecule by a center of
symmetry). The bond lengths and bond angles in the triꢀ
cyclic system of molecule 5b (Table 1) are similar to the
corresponding values for molecules 5a,c,d.27 The ethoxyꢀ
carbonyl substituent at the C(2) atom in molecule 5b, like
Table 1. Selected geometric parameters (bond lengths (d), bond angles (ω), and torsion angles (τ)) in molecule 5b
Parameter
Bond
Value
Parameter
Angle
Value
Parameter
Angle
Value
d/Å
ω/deg
ω/deg
N(1)—C(2)
C(2)—C(3)
C(3)—C(4)
1.338(3)
1.361(3)
1.431(3)
1.520(3)
1.527(2)
1.452(2)
1.522(2)
1.422(2)
1.369(3)
1.392(3)
1.519(3)
1.230(2)
1.388(3)
1.727(2)
1.743(3)
C(3)—C(4)—C(4a)
C(5)—O(6)—C(6a)
O(6)—C(5)—C(4a)
C(2)—N(1)—C(10b)
O(6)—C(6a)—C(7)
N(1)—C(2)—C(3)
O(6)—C(6a)—C(10a)
C(2)—C(3)—C(4)
C(4)—C(4a)—C(10b)
C(5)—C(4a)—C(10b)
O(4)—C(4)—C(3)
116.0(2)
117.4(2)
111.1(2)
119.7(2)
116.3(2)
123.6(2)
124.2(2)
119.9(2)
110.9(2)
109.2(2)
124.2(2)
119.7(2)
119.6(2)
109.1(2)
108.2(2)
C(6a)—C(7)—Cl(1)
C(8)—C(7)—Cl(1)
C(8)—C(9)—Cl(2)
C(10)—C(9)—Cl(2)
119.1(2)
119.8(2)
119.3(2)
119.5(2)
C(4)—C(4a)
C(4a)—C(10b)
C(10b)—N(1)
C(4a)—C(5)
C(5)—O(6)
O(6)—C(6a)
C(6a)—C(10a)
C(10a)—C(10b)
C(4)—O(4)
Angle
τ/deg
С(2)—C(11)—O(12)—C(13)
С(11)—O(12)—C(13)—C(14) 173.9(2)
O(11)—C(11)—O(12)—C(13)
С(3)—C(2)—C(11)—O(12)
N(1)—C(2)—C(11)—O(11)
С(5)—C(15)—O(16)—C(17)
С(15)—O(16)—C(17)—C(18) 176.7(2)
O(15)—C(15)—O(16)—C(17)
O(5)—C(5)—C(15)—O(15)
179.5(2)
–1.7(3)
–8.8(3)
–6.9(3)
179.9(2)
O(4)—C(4)—C(4a)
C(6a)—C(10a)—C(10b)
N(1)—C(10b)—C(4a)
C(4a)—C(10b)—C(10a)
C(5)—O(5)
С(7)—Cl(1)
С(9)—Cl(2)
4.3(3)
101.8(2)

1456
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
Mamedov et al.
Table 2. D—H...A hydrogen bond parameters (D is a donor and A is an acceptor) in the crystals of
compounds 5b and 9b
Bond
D–H
H...A
D...A
DHA
/deg
Symmetry
code
Å
5b
N(1)—H(1)...O(4)
0.86
0.82
0.98
0.98
0.86
2.00
2.08
2.80
2.49
2.39
2.772(2)
2.850(2)
3.742(2)
3.446(3)
2.700(3)
149
158
161
165
102
1 + x, y, z
1 – x, 1 – y, –z
x, 1 + y, z
1 + x, y, z
—
O(5)—H(5)...O(15)
C(4a)—H(4a)...Cl(1)
C(10b)—H(10b)...O(15)
N(1)—H(1)...O(11)
9b
N(1A)—H(1A)...O(7B)
N(1B)—H(1B)...O(7A)
O(15A)—H(15A)...O(10A)´
O(15B)—H(15B)...O(11B)´
O(15A)—H(15A)...N(16A)
O(15A)—H(15A)...O(17A)
N(1A)—H(1A)...O(7A)
N(1A)—H(1A)...O(15A)
N(1B)—H(1B)...O(7B)
N(1B)—H(1B)...O(15B)
O(10A)—H(10A)...O(4A)
O(10B)—H(10B)...O(4B)
O(15B)—H(15B)...O(16B)
O(15B)—H(15B)...N(16B)
C(6A)—H(6A)...O(11A)
C(6B)—H(6B)...O(12B)
0.86
0.86
0.82
0.82
0.82
0.82
0.86
0.86
0.86
0.86
0.82
0.82
0.82
0.82
0.98
0.98
2.25
2.37
2.39
2.39
2.53
1.94
2.31
2.48
2.31
2.50
1.70
1.69
1.96
2.52
2.25
2.22
2.98(1)
3.13(1)
2.79(1)
3.05(1)
2.95(2)
2.61(1)
2.66(2)
2.81(1)
2.65(1)
2.81(1)
2.44(2)
2.44(1)
2.64(1)
2.95(1)
2.75(2)
2.85(2)
144
147
111
138
113
140
104
104
104
103
150
151
140
113
110
121
x, y, –1 + z
x, y, 1 + z
1 + x, y, z
–1 + x, y, z
—
—
—
—
—
—
—
—
—
—
—
—
(10bS,4aR,5R)ꢀ5a, (10bR,4aR,5S)ꢀ5b and (10bS,4aS,5R)ꢀ5b,
(10bR,4aS,5S)ꢀ5c and (10bS,4aR,5R)ꢀ5c, (10bS,4aR,5R)ꢀ5d
and (10bR,4aR,5S)ꢀ5d were not detected in the crude
reaction mixtures. In addition, (10bR,4aS,5R)ꢀ5a and
(10bS,4aR,5S)ꢀ5a, (10bR,4aS,5R)ꢀ5c and (10bS,4aR,5S)ꢀ5c
are formed predominantly as the trans isomers, whereas
(10bR,4aR,5R)ꢀ5b and (10bS,4aS,5S)ꢀ5b, (10bR,4aR,5R)ꢀ5d
and (10bS,4aS,5S)ꢀ5d are formed mainly as the cis isoꢀ
mers. This is evidently associated with the presence of
the substituent (MeO or Cl) at position 5 of the starting
aromatic aldehyde or at position 9 of the resulting tricyꢀ
clic system.
To elucidate the influence of the electronꢀwithdrawing
substituents in salicylaldehyde on the pathway of the reacꢀ
tion under study, we performed the reaction of diethoxꢀ
alylacetone 3 with 3ꢀnitrosalicylaldehyde (4е). In this case,
the formation of the tricyclic benzo[e]pyrano[4,3ꢀb]ꢀ
pyridine structure is not observed. According to the TLC
data, the reaction affords two products, which strongly
differ in the Rf values. These products were separated by
column chromatography and were finally purified by reꢀ
crystallization. The IR spectrum of one product (orangeꢀ
red crystals, Rf 0.62) has absorption bands of the NH group
at 3290 cm–1 and of the OH group at 3360 cm–1, as well as
a broadened intense band at 1727 cm–1, which is indicaꢀ
tive of the presence of the ester group in this product. The
1H NMR spectrum of the latter product, unlike the specꢀ
tra of compounds 5a—d, does not show diagnostic signals
H(1)
N(1)
O(4)
O(5)
H(5)
O(15)
Fig. 5. Ribbons formed by the molecules via classical hydrogen
bonds in the crystal structure of compound 5b.

Tetrahydrobenzo[e]pyrano[4,3ꢀb]pyridines
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
1457
Scheme 4
for the protons of the AB system at δ 3.20 and 5.00 corꢀ
responding to the benzo[e]pyrano[4,3ꢀb]pyridine strucꢀ
ture. The H NMR spectrum has three doublets of douꢀ
oxyꢀ3´ꢀnitrophenyl)ꢀ1,4,5,6ꢀtetrahydropyridꢀ4ꢀone (9b)
(Scheme 4).
Actually, according to the Xꢀray diffraction data, the
reaction of diethoxalylacetone 3 with 3ꢀnitrosalicylaldeꢀ
hyde (4e) produces pyridinꢀ4ꢀone derivative 9b.
Compound 9b (Fig. 6), unlike the aboveꢀdescribed
compounds, crystallizes as a monocyclic isomer (in the
presence of the electronꢀwithdrawing nitro group as
the substituent in the phenyl group, the central pyran
ring of the molecule is cleaved). The crystals of compound
9b are noncentrosymmetric, and there are two indepenꢀ
dent molecules (A and B) per asymmetric unit. The chiral
centers in the independent molecules adopt opposite
configurations, i.e., the crystal is a racemic mixture.
The bond lengths and bond angles in the tetrahydroꢀ
pyridine heterocycle of molecules 9b(A) and 9b(B) are
equal within experimental error (Table 3); however, the
1
blets of the aromatic ring and doublets of triplets and
quartets of two ethoxycarbonyl groups along with broadꢀ
ened singlets of the OH and NH groups and signals for
the protons at the C(sp2) and C(sp3) atoms. The spectrum
has doublets at δ 5.65 and 6.62 (J = 2.0 Hz and J = 3.6 Hz,
respectively). The doublet at δ 5.65 belongs to the proꢀ
ton at the C(sp3) atom. The small spinꢀspin coupling
constant of the doublet compared to that observed for
the doublet of the AB system in the same region is indiꢀ
cative of the absence of the proton H(4a), which is apꢀ
parently associated with the enolization of the carbonyl
group of the ethoxalyl substituent. The spectroscopic data
are not contradictory to the structure 2ꢀethoxycarboꢀ
nylꢀ5ꢀ(2ꢀethoxyꢀ1ꢀhydroxyꢀ2ꢀoxoethylidene)ꢀ6ꢀ(2´ꢀhydrꢀ
C(8B)
O(8B)
C(9B)
C(7B)
O(7B)
C(3B)
C(2B)
O(4B)
O(16A)
C(12A)
O(11A)
C(17A)
C(13A)
N(1B)
C(4B)
C(5B)
C(18A)
C(19A)
N(16A)
C(6B)
O(12A)
C(11A)
O(15B)
C(16A)
C(15A)
C(10B)
O(17A)
C(14A)
C(6A)
O(10B)
C(11B)
C(14B)
C(15B)
C(16B)
O(10A)
O(12B)
O(15A)
O(16B)
C(19B)
C(18B)
C(5A)
O(11B)
C(12B)
C(13B)
N(16B)
N(1A)
C(17B)
O(4A)
C(4A)
C(3A)
O(17B)
C(2A)
O(7A)
C(7A)
O(8A)
C(8A)
C(9A)
Fig. 6. Molecular structures of two independent molecules of compound 9b in the crystal.

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Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
Mamedov et al.
Table 3. Selected geometric parameters (bond lengths (d), bond angles (ω), and torsion angles (τ)) in the independent
molecules of compound 9b
Parameter
9b(A)
9b(B)
Parameter
9b(A)
9b(B)
Bond
d/Å
Bond
d/Å
O(4)—C(4)
N(16)—C(16)
O(7)—C(7)
O(8)—C(7)
N(1)—C(6)
O(8)—C(8)
N(1)—C(2)
O(10)—C(10)
O(11)—C(11)
O(12)—C(11)
C(2)—C(3)
O(12)—C(12)
1.31(1)
1.49(1)
1.22(2)
1.30(2)
1.48(2)
1.48(2)
1.31(2)
1.31(1)
1.20(2)
1.30(2)
1.38(2)
1.48(3)
1.30(1)
1.45(2)
1.20(2)
1.30(2)
1.46(2)
1.42(2)
1.32(2)
1.28(1)
1.19(2)
1.26(2)
1.39(2)
1.43(3)
C(2)—C(7)
O(15)—C(15)
C(3)—C(4)
O(16)—N(16)
C(4)—C(5)
O(17)—N(16)
C(5)—C(6)
C(5)—C(10)
C(6)—C(14)
C(8)—C(9)
C(10)—C(11)
C(12)—C(13)
1.49(2)
1.35(1)
1.39(2)
1.19(2)
1.41(2)
1.20(2)
1.52(2)
1.40(2)
1.53(2)
1.39(3)
1.50(2)
1.35(3)
1.50(2)
1.36(1)
1.40(2)
1.21(2)
1.43(2)
1.18(2)
1.51(1)
1.39(1)
1.54(1)
1.40(3)
1.51(2)
1.31(3)
Angle
ω/deg
116(1)
116(1)
106.8(8) 108.2(8)
107.6(9)
113(1)
Angle
ω/deg
122(1)
120(1)
C(7)—O(8)—C(8)
117(1)
116(1)
C(6)—C(5)—C(10)
C(4)—C(5)—C(6)
C(5)—C(6)—C(14)
O(7)—C(7)—C(2)
O(7)—C(7)—O(8)
O(8)—C(8)—C(9)
C(5)—C(10)—C(11)
O(10)—C(10)—C(5)
O(10)—C(10)—C(11)
O(12)—C(11)—C(10)
O(15)—C(15)—C(14)
N(1)—C(2)—C(3)
N(1)—C(2)—C(7)
C(3)—C(4)—C(5)
O(4)—C(4)—C(5)
C(4)—C(5)—C(10)
126(1)
118(1)
C(11)—O(12)—C(12)
N(1)—C(6)—C(14)
N(1)—C(6)—C(5)
O(8)—C(7)—C(2)
C(2)—N(1)—C(6)
O(16)—N(16)—C(16)
O(16)—N(16)—O(17)
O(17)—N(16)—C(16)
O(11)—C(11)—O(12)
O(11)—C(11)—C(10)
O(12)—C(12)—C(13)
C(3)—C(2)—C(7)
114.2(8) 113.2(8)
110(1)
113(1)
121(1)
126(1)
109(2)
122(1)
121(1)
117(1)
111(1)
116.0(9) 115.7(9)
123(1) 122(1)
114(1) 113.4(9)
121(1)
126(1)
112(2)
127(1)
123(1)
111(1)
115(1)
122.8(8) 122.0(9)
118(1)
123(1)
119(1)
126(2)
123(2)
112(2)
123(1)
126.2(9) 124.3(9)
118(1)
118(1)
118(1)
120(1)
121(1)
124(2)
120(1)
113(2)
125(1)
O(15)—C(15)—C(16)
C(2)—C(3)—C(4)
O(4)—C(4)—C(3)
121.2(9)
121(1)
119(1) 116.7(9)
121(1)
123(1)
118(1)
117(1)
Angle
τ/deg
Angle
τ/deg
C(8)—O(8)—C(7)—O(7)
C(8)—O(8)—C(7)—C(2)
C(7)—O(8)—C(8)—C(9)
C(6)—N(1)—C(2)—C(3)
N(1)—C(2)—C(3)—C(4)
C(3)—C(4)—C(5)—C(6)
O(10)—C(10)—C(11)—O(11)
C(5)—C(10)—C(11)—O(12)
O(17)—N(16)—C(16)—C(15)
5(2)
–178(1)
–94(2)
–17(2)
–5(2)
–7(2)
175(1)
89(2)
13(1)
13(2)
–8(1)
7(2)
C(12)—O(12)—C(11)—O(11)
C(12)—O(12)—C(11)—C(10) –180(1)
–5(3)
0(3)
175(2)
C(11)—O(12)—C(12)—C(13)
C(2)—N(1)—C(6)—C(5)
C(2)—C(3)—C(4)—C(5)
C(4)—C(5)—C(6)—N(1)
C(5)—C(10)—C(11)—O(11)
O(10)—C(10)—C(11)—O(12)
–79(2) –168(3)
32(1)
8(1)
–28(1)
17(2) –170(2)
16(2) –169(1)
–33(1)
–15(2)
29(1)
11(1)
–159(2)
–169(1)
1(2)
14(2)
167(2)
O(17)—N(16)—C(16)—C(17) –178(2)
–14(2)
ethoxycarbonyl fragments at the C(10) atom in these molꢀ
ecules are twisted differently. In molecule 9b(A), the
hydroxy and oxyethyl groups are in the eclipsed conforꢀ
mation, whereas the hydroxy and carbonyl groups are in
the eclipsed conformation in molecule 9b(B) (see Fig. 6
and Table 3).
In both molecules, the tetrahydropyridine ring adopts
the Cꢀenvelop conformation (in molecule 9b(A), the
N(1)C(2)C(3)C(4)C(5) fragment is planar within 0.03(1)
Å, and the C(6) atom deviates from the plane by 0.41(1)
Å; in molecule 9b(B), the N(1)C(2)C(3)C(4)C(5) fragꢀ
ment is planar within 0.07(1) Å, and the C(6) atom deviꢀ
ates from the plane by –0.43(1) Å).
It should be noted that the conformations of molecules
9b(A) and 9b(B) in the crystal are stabilized by intramoꢀ
lecular hydrogen bonds (see Table 2). In addition, the
intermolecular hydrogen bonds stabilize the crystal structure.
Thus, molecules 9b form ribbons running along the 0a axis
of the crystal (the hydrogen bond parameters are given in
Table 2; the hydrogen bond network is shown in Fig. 7).
The massꢀspectrometric study of the second product
(10) (colorless crystals, Rf 0.45, m/z 306 М]+) provide

Tetrahydrobenzo[e]pyrano[4,3ꢀb]pyridines
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
1459
H(15B)
O(15B)
H(1B)
O(11B)´
N(1B)
O(7B)
N(1A)
O(15A)
O(10A)´
H(1A)
H(15A)
Fig. 7. Hydrogen bond network (indicated by dashed lines) in the crystal of 9b.
evidence that this product is generated as a result of the
elimination of the ethoxalyl group (—C(O)CO2Et) from
the initially formed product 9b under the conditions of the
reaction of diethoxalylacetone 3 with 3ꢀnitrosalicylaldeꢀ
hyde (4е) in EtOH.
The 1H NMR spectrum of this product has resonances
of the pronounced ABX system, which is apparently inꢀ
dicative of the hydrodiethoxalylation that occurs accordꢀ
ing to the scheme of the retroꢀaldol condensation in the
intermediate hemiketal A (Scheme 5) to form 2ꢀethoxyꢀ
carbonylꢀ6ꢀ(2´ꢀhydroxyꢀ3´ꢀnitrophenyl)ꢀ1,4,5,6ꢀtetraꢀ
hydropyridꢀ4ꢀone 10.
As can be seen from the aboveꢀgiven examples, salicylꢀ
aldehyde and its substituted derivatives containing elecꢀ
tronꢀdonating substituents in the ortho or para positions
with respect to the hydroxy group facilitate the pyran ring
closure in the intermediate pyridinꢀ4ꢀone derivatives conꢀ
taining the oꢀhydroxyphenyl and ethoxalyl groups at posiꢀ
tions 2 and 3, respectively, to form the tricyclic 1,4,4a,10bꢀ
tetrahydrobenzo[e]pyrano[4,3ꢀb]pyridine system. By conꢀ
trast, the reaction with 3ꢀnitrosalicylaldehyde (4е) stops
at the formation of the pyridinꢀ4ꢀone derivative. The inꢀ
tramolecular closure of the pyran ring does not occur due
to the deactivation of the hydroxy group by the nitro group.
Since compound 5a can be synthesized in two steps,
involving the synthesis of benzylimine 11 (in the first step)
and its reaction with diethoxalylacetone 3 (in the second
step), the reaction in the threeꢀcomponent system occurs,
apparently, through the intermediate formation of salicyꢀ
laldimine 12 (Scheme 6).
Scheme 5
Based on the results of the present study, which showed
that the tricyclic benzo[e]pyrano[4,3ꢀb]pyridine structure
is formed in the reactions with salicylaldehyde and its
3,5ꢀdichloroꢀ, 3ꢀmethoxyꢀ, and 5ꢀmethoxy derivatives,
whereas pyridinꢀ4ꢀone derivatives are produced in the reꢀ
action with 3ꢀnitrosalicylaldehyde, we suggest Scheme 7
for the reaction pathway.
Apparently, the reaction starts with the pyridinone ring
closure involving the imine bond between the salicylaldꢀ
imine moiety and one of the carbonyl groups followed by
the closure of the tricyclic system with the participation of
the OH group of salicylaldehyde and the electrophilic carꢀ

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Mamedov et al.
Scheme 6
bon atom of the ethoxalyl moiety. It should be noted that
the pyridinone ring can be closed not only through the
initial formation of the N(1)—C(2) bond (intermediate B)
but also through the formation of the C(4a)—C(10b) bond
(intermediate D).
An analysis of the published data showed that there are
different approaches to the synthesis of the benzo[е]pyraꢀ
no[4,3ꢀb]pyridine system depending on which bond in the
compound is involved in the ring closure or which method
for supplying necessary units is more accessible. These
approaches were exemplified with the fragments of the
structures IA,23,28 IB,15 IC,8—14,16—18 IIA,3—5,8—14,16—18,29
IIB,7 IIC,6,30,31 and IIIA.20
fused polycyclic systems. It was found that the reaction
pathway and the structures of the reaction products
that are formed in the threeꢀcomponent diethoxalylaceꢀ
tone—salicylaldehyde—ammonium acetate system are deꢀ
termined by the nature of the substituents in salicylaldeꢀ
hyde. The reactions with unsubstituted salicylaldehyde and
3,5ꢀdichloroꢀ, 3ꢀmethoxyꢀ, and 5ꢀmethoxysalicylaldeꢀ
hydes produce diastereomeric mixtures of benzopyranopyꢀ
ridines in different ratios. In the case of 3ꢀnitrosalicylalꢀ
dehyde, various functionalized pyridines are formed deꢀ
pending on the reaction conditions. New methods were
developed for the synthesis of the benzo[е]pyrano[4,3ꢀb]ꢀ
Hence, we showed for the first time that diethyl 2,4,6ꢀtriꢀ
oxoheptanedicarboxylate can be used as the synthetic
equivalent of the fiveꢀatom synthon for the synthesis of
Scheme 7

Tetrahydrobenzo[e]pyrano[4,3ꢀb]pyridines
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
1461
cold ethanol (2×15 mL), dried in air, and recrystallized from
PriOH. The yield of compound 5a was 0.15 g (42%), m.p.
178—179 °C. The melting point, the Rf value, and the spectroꢀ
scopic characteristics of compound 5a are identical to those of
the compound described above.
pyridine system, which can be classified as IID and IIIB
according to the retrosynthetic analysis.
7,9ꢀDichloroꢀ2,5ꢀdiethoxycarbonylꢀ5ꢀhydroxyꢀ4ꢀoxoꢀ
1,4,4a,10bꢀtetrahydrobenzo[e]pyrano[4,3ꢀb]pyridine (5b). A soꢀ
lution of 3,5ꢀdichlorosalicylaldehyde (4b) (0.38 g, 2 mmol) in
EtOH (10 mL) was added with stirring to a solution of ammoniꢀ
um acetate (0.2 g, 3.3 mmol) in EtOH (5 mL). The reaction
mixture was stirred for 10 min, and then a solution of diethoxalyꢀ
lacetone 3 (0.53 g, 2 mmol) in EtOH (10 mL) was added dropꢀ
wise. The reaction mixture was stirred at 45—50 °C for 12 h. The
solvent was removed in vacuo. The paleꢀyellow crystals that
formed were filtered off, washed with cold EtOH (2×15 mL),
dried in air, and recrystallized from EtOH. The yield of comꢀ
pound 5b was 0.28 g (34%), m.p. 162—164 °C. Found (%):
C, 59.20; H, 3.91; Cl, 16.57; N, 3.28. C18H17Cl2NO7. Calculatꢀ
ed (%): C, 50.23; H, 3.95; Cl, 16.51; N, 3.25. IR, ν/cm–1: 745,
776, 792, 823, 837, 865, 888, 909, 977, 1016, 1035, 1055, 1090,
1113, 1135, 1189, 1213, 1252, 1280, 1325, 1341, 1524, 1584,
1636, 1731, 1743, 3236, 3423. The ratio of the major to the
Experimental
The 1H NMR spectra were recorded on a Bruker Avanceꢀ
600 spectrometer operating at 600.13 MHz in CDCl3 for comꢀ
pounds 3, 5a, and 9b, in DMSOꢀd6 for compound 5b, and in
acetoneꢀd6 for compounds 5c,d, 10, and 11. The 13C NMR
spectra were measured on a Bruker WMꢀ400 spectrometer
(100.6 MHz) at 35 °C. The chemical shifts are given on the
δ scale with respect to the residual signals of the corresponding
solvents as the internal standard (δH 7.26 for CDCl3, δH 2.54 for
DMSO, and δH 2.09 for (CD3)2CO). The IR spectra were meaꢀ
sured on a Bruker Vectorꢀ22 spectrometer in KBr pellets in the
frequency range of 400—3600 cm–1. The course of the reactions
was monitored and the purity of the reaction products was
checked by TLC (Silufol UVꢀ254; diethyl ether—petroleum
ether—methanol, 2 : 1 : 0.1, as the eluent). The column chromaꢀ
tography was carried out on silica gel L100/160. The melting
points were determined on a Boetius hotꢀstage apparatus.
Diethyl 2,4,6ꢀtrioxoheptanedicarboxylate (3) was synthesized
according to a known procedure.32 M.p. 98—101 °C. After the
recrystallization from 80% ethanol, m.p. 100—101 °C (cf. lit.
data32: m.p. 102—103 °C). The IR spectrum of the crystalline
sample, ν/cm–1: 1730, 1650, 1640 (C=O), 3440 (OH). Accordꢀ
ing to the 1H NMR spectra in acetoneꢀd6 and CDCI3, comꢀ
pound 3 exists predominantly as dienol. 1H NMR (CDCl3), δ:
1.39 (t, 6 H, CH3, J = 7.1 Hz); 4.37 (q, 4 H, CH2, J = 7.1 Hz);
6.32 (s, 2 H, CH); 13.25 (s, 2 H, OH).
1
minor products was 5 : 1. The H NMR spectrum of the major
isomer in the crude product (DMSOꢀd6), δ: 1.26 (t, 3 H,
OCH2CH3, J = 7.1 Hz); 1.28 (t, 3 H, OCH2CH3, J = 6.7 Hz);
3.58 (d, 1 H, H(4a), J = 7.4 Hz); 4.22 (q, 2 H, OCH2CH3,
J = 7.1 Hz); 4.26—4.33 (m, 2 H, OCH2CH3); 5.02 (d, 1 H,
H(10b), J = 7.4 Hz); 5.23 (s, 1 H, H(3)); 7.41 (d, 1 H, H(10) or
H(8), J = 2.8 Hz); 7.50 (d, 1 H, H(8) or H(10), J = 2.8 Hz); 8.37
1
(br.s, 1 H, NH or OH); 8.83 (br.s, 1 H, NH or OH). H NMR
spectrum of the minor isomer in the crude product (DMSOꢀd6),
δ: 1.22 (t, 3 H, OCH2CH3, J = 7.0 Hz); 1.27 (t, 3 H, OCH2CH3,
J = 6.7 Hz); 3.12 (d, 1 H, H(4a), J = 15.8 Hz); 4.17 (q, 2 H,
OCH2CH3, J = 7.0 Hz); 4.26—4.33 (m, 2 H, OCH2CH3); 4.86
(d, 1 H, H(10b), J = 15.8 Hz); 5.56 (s, 1 H, H(3)); 7.40 (d, 1 H,
H(10) or H(8), J = 2.8 Hz); 7.41 (d, 1 H, H(8) or H(10), J= 2.8 Hz);
7.58 (br.s, 1 H, NH or OH); 8.00 (br.s, 1 H, NH or OH).
The pure major diastereomer was isolated from the diastereꢀ
omeric mixture, which was obtained with the use of 3,5ꢀdichloꢀ
rosalicylaldehyde, by the recrystallization from EtOH carried
out three times. The 1H NMR spectrum of the major product
(DMSOꢀd6), δ: 1.27 (t, 3 H, OCH2CH3, J = 7.1 Hz); 1.29 (t, 3 H,
OCH2CH3, J = 7.1 Hz); 3.60 (d, 1 H, H(4a), J = 7.3 Hz); 4.23
2,5ꢀDiethoxycarbonylꢀ5ꢀhydroxyꢀ4ꢀoxoꢀ1,4,4a,10bꢀtetraꢀ
hydrobenzo[e]pyrano[4,3ꢀb]pyridine (5a) was synthesized acꢀ
cording to a procedure described previously.4
2ꢀ(Hydroxyꢀ{[2ꢀ(hydroxyphenyl)methylene]amino}methyl)ꢀ
phenol (11). A solution of salicylaldehyde (0.49 g, 4 mmol) in
EtOH (5 mL) was added to a solution of ammonium acetate
(0.184 g, 2.4 mmol) in EtOH (20 mL). The reaction mixture was
stirred for 6 h and then concentrated under reduced pressure to
1/5 of the initial volume. The paleꢀyellow precipitate was sepaꢀ
rated and washed with EtOH (2×10 mL). The yield was 0.36 g
(73%), m.p. 257—259 °C. Found (%): C, 69.02; H, 5.41; N, 5.63.
C14H13NO3. Calculated (%): C, 69.15; H, 5.35; N, 5.76. IR,
ν/cm–1: 754, 797, 903, 992, 1019, 1043, 1150, 1239, 1275, 1392,
1492, 1592, 1628, 3048, 3253 (br). 1H NMR (acetoneꢀd6), δ:
6.49 (s, 1 H, CHOH); 6.76—7.50 (m, 10 H, 2 C6H4 + 2 OH);
8.84 (s, 1 H, CH=N); 13.19 (br.s, 1 H, OH).
Synthesis of tetrahydrobenzo[e]pyrano[4,3ꢀb]pyridine 5a with
the use of compound 11. A solution of diethoxalylacetone (0.26 g,
1 mmol) in EtOH (10 mL) was added to a solution of imine 11
(0.24 g, 1 mmol) in EtOH (20 mL). The reaction mixture was
refluxed for 3 h. Then the most part of the solvent was distilled
off in vacuo, and white crystals were filtered off, washed with
(q, 2 H, OCH2CH3, J = 7.1 Hz); 4.30 and 4.32 (m, 2 H, AB part
3
of the ABX3 system, OCHAHBCH3,X
,
2JAB = 10.9 Hz, JAX
=
= 3JBX = 7.1 Hz); 5.02 (dd, 1 H, H(10b), J = 7.3 Hz, J = 4.9 Hz);
5.24 (d, 1 H, H(3), J = 1.6 Hz); 7.44 (d, 1 H, H(10) or H(8),
J = 2.4 Hz); 7.55 (d, 1 H, H(8) or H(10), J = 2.4 Hz); 8.48 (br.s,
1 H, OH); 8.93 (dd, 1 H, NH, J = 4.9 Hz, J = 1.6 Hz). The
13C{1H} NMR spectrum of the major product (DMSOꢀd6), δ:
13.47 (qt, CH3CH2O, J = 127.4 Hz, J = 2.4 Hz); 13.49
(qt, CH3CH2O, J = 127.4 Hz, J = 2.4 Hz); 45.79 (dd, C(4a) or
C(10b), J = 134.0 Hz, J = 3.6 Hz); 45.97 (d, C(10b) or C(4a),
J = 150.79 Hz); 60.66 (tq, CH3CH2O, J = 147.2 Hz, J = 4.2 Hz);
62.15 (tq, CH3CH2O, J = 149.6 Hz, J = 4.2 Hz); 94.12 (d, C(5),
J = 4.8 Hz); 98.33 (dd, C(3), J = 170.6 Hz, J = 4.2 Hz); 121.72
(d, C(7), J = 3.6 Hz); 124.02 (dd, C(9), J = 8.1 Hz, J = 5.1 Hz);
124.45 (dd, C(10), J = 167.0 Hz, J = 5.4 Hz); 124.77 (dd, C(10a),
J = 4.2 Hz, J = 3.6 Hz); 128.92 (dd, C(8), J = 171.8 Hz, J = 6.0 Hz);
146.93 (d, C(2), J = 6.6 Hz); 147.45 (d, C(6a), J = 7.2 Hz);
162.00 (t, C(O)O, J = 3.0 Hz); 166.60 (t, C(O)O, J = 3.0 Hz);

1462
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
Mamedov et al.
187.39 (dd, C=O, J = 5.4 Hz, J = 6.6 Hz). The 13C{1H} NMR
spectrum of the minor product (DMSOꢀd6), δ: 13.40 (CH3CH2O);
13.41 (CH3CH2O); 47.47 (C(4a) or C(10b)); 48.70 (d, C(10b) or
C(4a)); 61.42 (CH3CH2O); 62.15 (CH3CH2O); 95.00 (C(5));
102.0 (C(3)); 122.31 (C(7)); 123.06 (dd, C(9)); 125.64 (C(10));
128.02 (C(10a)); 133.58 (C(8)); 147.42 (C(2)); 148.40 (C(6a));
162.08 (C(O)O); 166.99 (C(O)O); 190.07 (C=O).
reaction products (acetoneꢀd6), δ: 1.27 (t, 3 H, OCH2CH3,
J = 7.1 Hz); 1.28 (t, 3 H, OCH2CH3, J = 7.1 Hz); 1.32 (t, 3 H,
OCH2CH3, J = 7.2 Hz); 1.35 (t, 3 H, OCH2CH3, J = 7.3 Hz);
3.18 (d, 1 H, H(4a), J = 16.1 Hz); 3.66 (d, 1 H, H(4a), J = 6.6 Hz);
3.71 (s, 3 H, CH3O); 3.81 (s, 3 H, CH3O); 4.22—4.33 (m, 8 H,
4 OCH2CH3); 4.95 (d, 1 H, H(10b), J = 16.1 Hz); 5.22 (d, 1 H,
H(10b), J = 6.6 Hz); 5.60 (s, 1 H, H(3)); 5.40 (s, 1 H, H(3));
6.81 (d, 1 H, H(7), J = 8.9 Hz); 6.88 (dd, 1 H, H(8), J = 8.9 Hz,
J = 2.8 Hz); 7.29 (d, 1 H, H(10), J = 2.8 Hz); 6.83 (d, 1 H, H(7),
J = 6.6 Hz); 7.01 (dd, 1 H, H(8), J = 6.6 Hz, J = 2.6 Hz); 7.27
(d, 1 H, H(10), J = 2.6 Hz); 6.12, 6.44, 6.69, 8.37 (br.s, NH + OH
of the cis and trans products; it is impossible to unambiguously
assign the signals in this region).
Threeꢀcomponent condensation of diethyl 2,4,6ꢀtrioxohepꢀ
tanedicarboxylate (3) with 3ꢀnitrosalicylaldehyde (4e) in the presꢀ
ence of ammonium acetate. A solution of 3ꢀnitrosalicylaldehyde
(4e) (0.7 g, 4 mmol) in EtOH (5 mL) was added with stirring to
a solution of ammonium acetate (0.185 g, 2.4 mmol) in EtOH
(10 mL). The reaction mixture was stirred for 10 min. Then
a solution of diethoxalylacetone 3 (0.52 g, 2 mmol) in EtOH
(10 mL) was added dropwise, and the mixture was stirred at
50—55 °C for 10 h. The solvent was removed in vacuo, and the
viscous brown residue, which consisted mainly of two comꢀ
pounds (TLC data; Silufol UVꢀ254, diethyl ether—petroleum
ether—methanol, 2 : 1 : 0.1, as the eluent) with Rf 0.62 and
Rf 0.45, was separated by column chromatography on silica gel
(diethyl ether—propanꢀ2ꢀol, 15 : 1, as the eluent). 2ꢀEthoxycarꢀ
bonylꢀ5ꢀ(2ꢀethoxyꢀ1ꢀhydroxyꢀ2ꢀoxoethylidene)ꢀ6ꢀ(2´ꢀhydroxyꢀ
3´ꢀnitrophenyl)ꢀ1,4,5,6ꢀtetrahydropyridꢀ4ꢀone (9b) was obꢀ
tained as orangeꢀred crystals in a yield of 0.09 g (22%), and
2ꢀethoxycarbonylꢀ6ꢀ(2´ꢀhydroxyꢀ3´ꢀnitrophenyl)ꢀ1,4,5,6ꢀtetraꢀ
hydropyridꢀ4ꢀone (10) was obtained as colorless crystals in a yield
of 0.19 g (63%) .
2,5ꢀDiethoxycarbonylꢀ5ꢀhydroxyꢀ7ꢀmethoxyꢀ4ꢀoxoꢀ
1,4,4a,10bꢀtetrahydrobenzo[e]pyrano[4,3ꢀb]pyridine (5c). A soꢀ
lution of 3ꢀmethoxysalicylaldehyde (4c) (0.3 g, 2 mmol) in EtOH
(5 mL) was added with stirring to a solution of ammonium aceꢀ
tate (0.092 g, 1.2 mmol) in EtOH (10 mL). The reaction mixture
was stirred for 10 min. Then a solution of diethoxalylacetone 3
(0.26 g, 1 mmol) in EtOH (10 mL) was added dropwise, and the
reaction mixture was stirred at 50—55 °C for 70 h. The solvent
was removed in vacuo using a water jetꢀpump. The resulting
viscous brown residue was separated on a chromatographic colꢀ
umn (diethyl ether—propanꢀ2ꢀol, 20 : 1 → 5 : 1, as the eluent).
Paleꢀyellow crystals were recrystallized from toluene. Compound
5c was obtained in a yield of 0.09 g (23%), m.p. 128—129 °C.
Found (%): C, 68.81; H, 6.38; N, 4.21. C19H21NO8. Calculatꢀ
ed (%): C, 68.88; H, 6.34; N, 4.23. IR, ν/cm–1: 748, 781, 829,
847, 899, 927, 973, 1037, 1083, 1129, 1215, 1266, 1325, 1369,
1394, 1422, 1452, 1466, 1495, 1518, 1586, 1633, 1741, 2836,
2872, 2936, 2980, 3320, 3434. The ratio of the diastereomers
1
was ~1 : 2, with the trans isomer predominating. The H NMR
spectrum of the minor product (acetoneꢀd6), δ: 1.29 (t, 3 H,
OCH2CH3, J = 6.7 Hz); 1.31 (t, 3 H, OCH2CH3, J = 6.7 Hz);
3.67 (d, 1 H, H(4a), J = 6.5 Hz); 3.85 (s, 3 H, OCH3);
4.30—4.40 (m, 4 H, 2 OCH2CH3); 5.25 (d, 1 H, H(10b), J = 6.5 Hz);
5.36 (s, 1 H, H(3)); 6.66 (d, 1 H, H(8) or H(10), J = 8.0 Hz);
6,78 (dd, 1 H, H(9), J = 8.0 Hz, J = 8.0 Hz); 7.24 (d, 1 H, H(10)
1
or H(8), J = 8.0 Hz). H NMR of the major product (acetoneꢀ
d6), δ: 1.22 (t, 3 H, OCH2CH3, J = 7.0 Hz); 1.27 (t, 3 H,
OCH2CH3, J = 6.7 Hz); 3.12 (d, 1 H, H(4a), J = 15.8 Hz); 3.77
(s, 3 H, OCH3); 4.17 (q, 2 H, OCH2CH3, J = 7.0 Hz); 4.30—4.40
(m, 2 H, OCH2CH3); 4.86 (d, 1 H, H(10b), J = 15.8 Hz); 5.56
(s, 1 H, H(3)); 6.86 (d, 1 H, H(8) or H(10), J = 7.0 Hz); 6.92
(d, 1 H, H(10) or H(8), J = 7.3 Hz); 6.93 (dd, 1 H, H(9), J = 7.3 Hz,
J = 7.0 Hz); 7.58, 8.00, 8.37, 8.83 (br.s, NH + OH of the major
and minor products; it is impossible to unambiguously assign the
signals in this region).
2,5ꢀDiethoxycarbonylꢀ5ꢀhydroxyꢀ9ꢀmethoxyꢀ4ꢀoxoꢀ
1,4,4a,10bꢀtetrahydrobenzo[e]pyrano[4,3ꢀb]pyridine (5d). A soꢀ
lution of 5ꢀmethoxysalicylaldehyde (4d) (0.3 g, 2 mmol) in EtOH
(5 mL) was added with stirring to a solution of ammonium aceꢀ
tate (0.092 g, 1.2 mmol) in EtOH (10 mL). The reaction mixture
was stirred for 10 min. Then a solution of diethoxalylacetone 3
(0.26 g, 1 mmol) in EtOH (10 mL) was added dropwise, and
the mixture was stirred at 50—55 °C for 20 h. The solvent
was removed in vacuo, and the viscous red residue was separated
on a chromatographic column (diethyl ether—propanꢀ2ꢀol,
20 : 1 → 5 : 1, as the eluent). Paleꢀyellow crystals were recrystalꢀ
lized from toluene. Compound 5d was obtained in a yield of
0.14 g (36%), m.p. 137—140 °C. Found (%): C, 68.81; H, 6.38;
N, 4.21. C19H21NO8. Calculated (%): C, 68.88; H, 6.34; N, 4.23.
IR, ν/cm–1 (KBr pellet): 748, 781, 829, 847, 899, 927, 973, 1037,
1083, 1129, 1215, 1266, 1325, 1369, 1394, 1422, 1452, 1466,
1495, 1518, 1586, 1633, 1741, 2836, 2872, 2936, 2980, 3320,
3434. The ratio of the diastereomers was ~2 : 1, with the cis isomer
predominating. The 1H NMR spectrum of the mixture of the
Compound 9b. M.p. 117—119 °C. Found (%): C, 53.05;
H, 4.32; N, 6.75. C18H18N2O9. Calculated (%): C, 53.21;
H, 4.46; N, 6.89. IR, ν/cm–1: 523, 597, 663, 743, 755, 815, 854,
862, 912, 1015, 1050, 1092, 1119, 1207, 1259, 1298, 1337, 1535,
1588, 1611, 1727, 2726, 3290, 3364. 1H NMR (CDCl3), δ: 1.25
(t, 3 H, OCH2CH3, J = 7.4 Hz); 1.32 (t, 3 H, OCH2CH3,
J = 7.4 Hz); 4.15—4.24 (m, 2 H, OCH2CH3); 4.25—4.32 (m, 2 H,
OCH2CH3); 5.77 (s, 1 H, H(3)); 6.69 (br.s, 1 H, H(6)); 6.85
(br.s, 1 H, NH); 6.96 (dd, 1 H, H(5´), J = 8.4 Hz, J = 7.3 Hz);
7.26 (br.s, 1 H, HOC(2´)); 7.41 (d, 1 H, H(4´) or H(6´), J = 7.3 Hz);
8.06 (d, 1 H, H(6´) or H(4´), J = 8.4 Hz); 11.28 (br.s, 1 H,
1
HOC(5´)). H NMR (acetoneꢀd6), δ: 1.25 (t, 3 H, OCH2CH3,
J = 7.0 Hz); 1.29 (t, 3 H, OCH2CH3, J = 7.0 Hz); 4.18 (q, 2 H,
OCH2CH3, J = 7.0 Hz); 4.29 (q, 2 H, OCH2CH3, J = 7.0 Hz);
5.65 (d, 1 H, H(6), J = 2.0 Hz); 6.62 (d, 1 H, H(3), J = 3.6 Hz);
7.10 (dd, 1 H, H(5´), J = 8.6 Hz, J = 7.6 Hz); 7.50 (br.s, 1 H,
NH); 7.54 (dd, 1 H, H(4´), J = 7.6 Hz, J = 1.3 Hz); 8.10 (dd, 1 H,
H(6´), J = 8.6 Hz, J = 1.3 Hz); 11.11 (br.s, 1 H, OH).
Compound 10. M.p. 173—175 °C. Found (%): C, 54.77;
H, 4.50; N, 9.22. C14H14N2O6. Calculated (%): C, 54.90;
H, 4.61; N, 9.15. IR, ν/cm–1: 420, 551, 742, 781, 859, 968,
1012, 1068, 1097, 1145, 1196, 1246, 1297, 1357, 1376, 1515,
1
1535, 1586, 1625, 1733, 3110, 3285. H NMR (acetoneꢀd6), δ:
1.33 (t, 3 H, OCH2CH3, J = 6.9 Hz); 4.35 (q, 2 H, OCH2CH3,
J = 6.9 Hz); protons of C(5)H2 resonate as an AB part of an
ABX system; 2.73 (H(5)A, JAB = 16.1 Hz, JAX = 5.6 Hz);
2.90 (H(5)B, JAB = 16.1 Hz, JBX = 9.9 Hz); 5.31 (H(6)X,
JAX = 5.6 Hz, JBX = = 9.9 Hz); 5.61 (s, 1 H, H(3)); 7.05 (dd, 1 H,

Tetrahydrobenzo[e]pyrano[4,3ꢀb]pyridines
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
1463
H(5´), J = 7.7 Hz, J = 7.0 Hz); 7.47 (br.s, 1 H, NH); 7.69
(d, 1 H, H(6´), J = 7.0 Hz); 8.13 (d, 1 H, H(4´), J = 7.7 Hz);
11.28 (br.s, 1 H, OH).
The single crystals of compounds 5b and 9b were studied at the
Department of Xꢀray Diffraction Studies of the Center of Colꢀ
laborative Research on the basis of the Laboratory of Xꢀray Difꢀ
fraction Methods of the A. E. Arbuzov Institute of Organic and
Physical Chemistry, the Kazan Research Center of the Russian
Academy of Sciences. Selected geometric parameters of moleꢀ
cules 5b and 9b are given in Tables 1 and 3, respectively.
Xꢀray diffraction study. The results of the Xꢀray diffraction
study of compounds 5a,c,d have been reported previously.27 The
crystallographic characteristics and the Xꢀray data collection
and refinement statistics for compounds 5b and 9b are given in
Table 4. The Xꢀray diffraction data sets for compounds 5b and 9b
were collected on an automated fourꢀcircle EnrafꢀNonius CADꢀ4
diffractometer (graphite monochromator, CuꢀKα radiation,
λ = 1.54184 Å, 293 K, ωꢀscanning technique). The intensities of
three check reflections showed no decrease in the course of Xꢀray
data collection. The unit cell parameters were determined, the
intensities of reflections were measured, and the Xꢀray diffracꢀ
tion data were processed with the use of the MolEN program33
on a DEC AlphaStation 200. All structures were solved by direct
methods with the use of the SIR program34 and refined first
isotropically and then anisotropically using the SHELXLꢀ9735
and WinGX36 program packages. The hydrogen atoms of moleꢀ
cules 5b and 9b were positioned geometrically and refined using
a riding model. All figures were drawn and the intermolecular
interactions were analyzed with the use of the PLATON proꢀ
gram.37 The atomic coordinates and structural parameters for
compounds 5b and 9d were deposited with the Cambridge Strucꢀ
tural Database (CCDC 626991 (5b) and CCDC 640757 (9b)).
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 07ꢀ03ꢀ00613ꢀa)
and the Federal Target Program "Research and Deꢀ
velopment in Priority Fields of Science and Technology
in Russia in 2007—2012" (Government State Contract
No. 02.512.11.2237).
References
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Color, crystal shape
Yellowish,
prismatic
C18H17Cl2NO7
Triclinic
P–1
Colorless,
prismatic
C18H18N2O9
Monoclinic
P21
8.710(6)
20.24(2)
10.756(8)
90
92.98(6)
90
1894(3)
4*
406.34
1.43
10.0
—**
4.1
68.0
2547
(0.1879)
1844
Molecular formula
Crystal system
Space group
a/Å
b/Å
c/Å
α/deg
β/deg
6.701(2)
8.785(3)
17.499(2)
81.56(7)
78.90(6)
76.65(6)
977.9(6)
2
430.23
1.46
33.6
Empirical
2.6
γ/deg
V/Å3
Z
Molecular weight
dcalc/g cm–3
μ/cm–1
Absorption correction
θ
θ
min/deg
max/deg
69.9
3607
(0.1104)
2979
Number of measured
reflections (Rint
)
Number of reflections
with I > 2σ(I)
Number of refined
parameters
Final R factors
254
527
R1 = 0.0516,
wR2 = 0.1585
R1 = 0.1033,
wR2 = 0.3032
* Two independent molecules A and B.
** The corrections was not applied.

1464
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
Mamedov et al.
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Received July 31, 2008;
in revised form February 13, 2009