Regio- and diastereoselective synthesis of N-substituted 2-acyl-3-aryl-3,5-dihydrofuro[3,2-c]pyridin-4(2H)-ones

Article abstract of DOI:10.1007/s10593-020-02832-z

[Figure not available: see fulltext.] The three-component condensation of pyridinium acylmethylides generated in situ with aromatic aldehydes and 4-hydroxy-6-methylpyridones gave a series of 2-acyl-3-aryl-3,5-dihydrofuro[3,2-c]pyridin-4(2H)-ones. The reaction proceeds diastereoselectively with the formation of trans-isomers and represents a cascade process involving the Knoevenagel condensation, the carbo-Michael reaction, and intramolecular nucleophilic substitution.

Full text of DOI:10.1007/s10593-020-02832-z

DOI 10.1007/s10593-020-02832-z
Chemistry of Heterocyclic Compounds 2020, 56(11), 1423–1428
Regio- and diastereoselective synthesis of N-substituted
2-acyl-3-aryl-3,5-dihydrofuro[3,2-c]pyridin-4(2H)-ones
Evgeny А. Kvetkin1, Dmitry V. Osipov1, Pavel E. Krasnikov1,
Vitaly А. Osyanin1*, Yuri N. Klimochkin1
1 Samara State Technical University,
244 Molodogvardeyskaya St., Samara 443100, Russia; е-mail: VOsyanin@mail.ru
Submitted July 12, 2020
Accepted after revision August 3, 2020
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2020, 56(11), 1423–1428
The three-component condensation of pyridinium acylmethylides generated in situ with aromatic aldehydes and 4-hydroxy-
6-methylpyridones gave a series of 2-acyl-3-aryl-3,5-dihydrofuro[3,2-c]pyridin-4(2H)-ones. The reaction proceeds diastereoselectively
with the formation of trans-isomers and represents a cascade process involving the Knoevenagel condensation, the carbo-Michael
reaction, and intramolecular nucleophilic substitution.
Keywords: 2-acyl-3-aryl-3,5-dihydrofuro[3,2-c]pyridin-4(2H)-ones, pyridinium ylides, MIRC reaction, multicomponent reactions.
The Michael-initiated ring-closure (MIRC) transfor-
mations1 are widely used for the preparation of cyclo-
propane derivatives from electron-deficient olefins and
C-nucleophiles containing a good leaving group in their
structure.2 Similar processes are used much less frequently
for accessing heterocycles, in particular chromeno-
quinolines,3 derivatives of dihydrofurans,4 and their
condensed analogs.5 Among the latter, 3,5-dihydrofuro-
[3,2-c]pyridin-4(2H)-ones are of great interest as key
fragments of 4-hydroxy-2-pyridone alkaloids with a wide
range of biological action,6 for example, citridone A,7
furopyridine antibiotic CJ-16,170,8 polyketide huaspenone
D,9 and campyridone A10 (Fig. 1). Likewise, inhibitors of
the mitochondrial complex I were described among the
4-hydroxy-2-pyridone alkaloids.11
In this work, we have shown that the reactions of
4-hydroxy-6-methylpyridones 1 with aromatic aldehydes 2
and pyridinium acylmethylides generated in situ from the
corresponding pyridinium salts 3 leads to the formation of
trans-2-acyl-3-aryl-3,5-dihydrofuro[3,2-c]pyridin-4(2H)-ones
4a–j in 54–79% yields (Scheme 1). The formation of cis-
isomers was not observed. The reaction was carried out in
pyridine at 100°C in an argon atmosphere. Carrying out the
Figure 1. Alkaloids with the 3,5-dihydrofuro[3,2-c]pyridin-
4(2H)-one fragment.
0009-3122/20/56(11)-1423©2020 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2020, 56(11), 1423–1428
Scheme 1
Br–
Br–
O
O
O
R3
OH
N
+
N
+N
O
R3
CHO
O
O
3
+
R2
Ph
Py, 100°C, 8 h, argon
– Py·HBr, – H2O
54%
Py, 100°C, 8 h, argon
– Py·HBr, – H2O
Me
O
R2
Me
N
O
R1
2
Me
N
Bn
O
1
R1
4a–i
4j
4 a R1 = R3 = Ph, R2 = H (57%); b R1 = R3 = Ph, R2 = 4-Cl (77%);
c R1 = R3 = Ph, R2 = 4-MeO (64%); d R1 = 4-MeOC6H4, R2 = H, R3 = Ph (65%);
e R1 = Ph, R2 = H, R3 = 3,4,5-(MeO)3C6H2 (70%); f R1 = 3,4-(MeO)2C6H3CH2, R2 = 2-NO2, R3 = Ph (75%);
g R1 = pyridin-3-yl, R2 = H, R3 = Ph (68%); h R1 = 4-MeOC6H4, R2 = 4-Cl, R3 = 1-Ad (79%);
i R1 = 4-MeOC6H4, R2 = 4-MeO, R3 = 1-Ad (62%)
COPh
OH
CHO
O
Br–
+N
O
+
+
4b (40%) +
Cl
Py, 100°C, air
Me
N
Bn
O
Ph
Me
N
Bn
O
Cl
5 (32%)
reaction in the presence of atmospheric oxygen leads to
partial aromatization of the dihydrofuran derivatives, which
was shown in the preparation of compound 4b. Substituted
furo[3,2-c]pyridin-4(5H)-one 5 was also isolated by column
chromatography in 32% yield (Scheme 1). Higher yields
were observed when using aromatic aldehydes containing
acceptor groups (compounds 4b,f,h), due to the greater
electrophilic activity of the carbonyl carbon atom in the
Knoevenagel condensation. In the case of the pyridinium
salt based on 2-bromo-1-indanone, dihydrofuropyridine
with a spirocyclic structure 4j was synthesized.
In addition, we tried to use sulfur ylides as Michael
donors in this condensation. However, in the case of
dimethyl phenacyl sulfonium bromide, benzaldehyde, and
1-benzyl-4-hydroxy-6-methylpyridin-2(1H)-one, the yield
of product 4а was comparable and amounted to 50%.
The precursors 4-hydroxy-6-methylpyridin-2(1H)-ones
1 were obtained from 4-hydroxy-6-methyl-2H-pyran-2-one
and primary amines by heating under reflux in H2O.
Attempts to combine the step of the formation of
pyridinones 1 and their subsequent condensation with
aldehydes and pyridinium salts into a four-component
reaction were unsuccessful. Thus, in the case of 4-chloro-
benzaldehyde, 4-methoxybenzylamine, phenacyl pyridinium
bromide, and 4-hydroxy-6-methyl-2H-pyran-2-one, trans-
2,3-dihydro-4H-furo[3,2-c]pyran-4-one 6 described in the
literature was isolated in a 45% yield (Scheme 2). It was
previously obtained from the indicated compounds in the
absence of 4-methoxybenzylamine.12 It should also be
noted that we could not find literature examples of the
transformation of 2,3-dihydro-4H-furo[3,2-c]pyran-4-ones
into 3,5-dihydrofuro[3,2-c]pyridin-4(2H)-ones.
In the 1H NMR spectra of compounds 4a–h, two
doublets in the ranges of 4.55–4.77 (at 5.60 ppm for
compound 4f) and 5.43–6.01 ppm with vicinal SSCCs of
4.1–4.8 Hz correspond to hydrogen atoms 3-СН and 2-CH
of the dihydrofuran ring in the trans configuration to each
1
other.5b,13 In the H NMR spectrum of spirocyclic dihydro-
furopyridine 4j, there is one singlet signal at 4.84 ppm
corresponding to the methine proton 3-CH. In the spectra
of products 4a–j, the protons of the methyl group and
proton H-7 appear as singlet signals at 2.15–2.32 and 5.90–
6.15 ppm, respectively. In the 13C NMR spectra, signals in
21.4–21.6, 44.2–50.7, 89.5–92.1, 95.3–96.2, 107.3–110.0,
and 149.1–150.0 ppm ranges, which correspond to the
methyl carbon atom and carbon atoms at positions 3, 2, 7,
3а, and 6 of the dihydrofuro[3,2-c]pyridinone fragment,
respectively. The lactam carbon atom C-4 resonates at
160.5–161.1 ppm, and the carbon atom C-7a, bonded to the
oxygen atom, at 166.8–167.3 ppm. In the case of aryl
derivatives 4a–g, the carbonyl carbon atom appears in the
region of 192.0–193.6 ppm.
Considering the mechanism of the reaction (Scheme 3),
it appears that the Knoevenagel condensation between
4-hydroxy-6-methylpyridone 1 and aromatic aldehyde 2
occurs first, followed by the Michael addition of the
carbonyl-stabilized pyridinium ylide. In this case, the
solvent pyridine not only catalyzes the Knoevenagel
condensation, but also promotes the generation of the
corresponding ylide in a low concentration. The resulting
Scheme 2
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Chemistry of Heterocyclic Compounds 2020, 56(11), 1423–1428
Scheme 3
H
R3
C
+
+
+
O
N
N
N
N
COR3
Ar
COR3
Ar
O–
N
O
N
O
Ar
Py
1 + 2
C
Me
O
Me
O
Me
O
R1
R1
R1
A
R2
5-exo-tet
(Path 1)
5-exo-tet
(Path 2)
3-exo-tet
(Path 3)
5-endo-trig
(Path 4)
Ar =
COR3
COR3
O
N
O
Ar
O
O
N
N
COR3
Ar
Ar
COR3
O
Me
Me
N
O
Ar
Me
N
O
Me
O
R1
R1
B
C
D
R1
4
R1
zwitterionic intermediate A can undergo transformations
via several routes. Intramolecular nucleophilic substitution
of pyridine (path 1) as a result of 5-exo-tet cyclization will
lead to the final 3,5-dihydrofuro[3,2-c]pyridin-4(2H)-ones
4a–j.
The stereochemistry of the SN2 process requires that the
attack by a negatively charged oxygen atom of the
electrophilic center occurs from the side opposite to the
leaving group. Based on this, it can be assumed that large
acyl and aryl groups, for steric reasons, should be in a
transition state in an antiperiplanar position, which
ultimately leads to thermodynamically more stable trans-
isomers (Fig. 2).
Figure 3. Selected correlations in the 1H–13C HMBC spectrum of
compound 4h.
The presence of three cross peaks with protons at
positions 2, 3, and 7 indicates the formation of products 4. In
the case of compounds B, two such cross peaks (С-4/H-3 and
С-4/H-5) would be expected. Although Michael adducts
from pyridinium ylides and electron-deficient olefins are
often stabilized by 3-exo-tet (path 3) or 5-endo-trig
cyclization (path 4),14 the formation of cyclopropane C or
indolizine D derivatives is also not observed in this case,
which is apparently due to the disadvantageous loss of
conjugation energy (Scheme 3).15
To conclude, we have demonstrated that the anionic
domino reaction between pyridinium acylmethylides,
aromatic aldehydes, and N-substituted 4-hydroxy-6-methyl-
pyridones proceeds regio- and diastereoselectively and
leads to the formation of 2-acyl-3-aryl-3,5-dihydrofuro[3,2-c]-
pyridin-4(2H)-ones.
Experimental
Figure 2. Newman projections of intermediate A.
1H and 13C NMR (400 and 100 MHz, respectively),
1
1
The probable participation of the lactam carbonyl group
in heterocyclization is not realized in this case. Since the
isomeric 3,5-dihydrofuro[3,2-c]pyridin-4(2H)-ones 4 and
3,7-dihydrofuro[2,3-b]pyridin-4(2H)-ones B cannot be
reliably distinguished by routine NMR spectra due to the
proximity of the corresponding signals,7,8,13b two-
dimensional 1H–13C HMBC spectra were recorded for
compounds 4c,h. Figure 3 shows the most significant
correlations through 2-3 covalent bonds for the C-7a atom.
DEPT-135, as well as H–13C HMBC, H–13C HMQC,
NOESY (mixing time 0.7 s), and COSY (for compounds
4с,h) spectra were acquired on a JEOL JNM-ECX400
spectrometer in CDCl3 with the residual solvent signal
(7.26 ppm for Н nuclei and 77.0 ppm for 13С nuclei)
1
serving as internal standard. Elemental analysis was
performed on a Euro Vector EA-3000 CHNS-analyzer.
Melting points were determined by the capillary method on
an SRS OptiMelt MPA100 apparatus. Monitoring of the
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Chemistry of Heterocyclic Compounds 2020, 56(11), 1423–1428
reaction progress and assessment of the purity of
(2H, d, J = 7.6, H Ar). 13C NMR spectrum, δ, ppm: 21.8
(CH3); 46.9 (CH2); 95.9 (7-CH); 112.7; 126.3 (2CH); 127.5
(CH); 127.8 (2CH); 128.0; 128.2 (2CH); 129.0 (2CH);
129.6 (2CH); 132.3 (2CH, C); 132.7 (CH); 134.7; 136.4;
137.1; 146.4; 147.6; 160.1; 160.4; 184.6 (C=O). Found, %:
C 73.98; H 4.50; N 2.97. C28H20ClNO3. Calculated, %:
C 74.09; H 4.44; N 3.09.
synthesized compounds were done by TLC on Merck
Silica gel 60 F254 plates, eluent СHCl3–МеОН, 98:2,
visualization with UV light or by iodine stain. Merck Silica
gel 60 (0.04–0.063 mm) was used for column chromato-
graphy.
Synthesis of 3,5-dihydrofuro[3,2-c]pyridin-4(2H)-ones
4a–j (General method). A mixture of 4-hydroxy-6-methyl-
pyridin-2(1Н)-one 1 (2.5 mmol), aldehyde 2 (2.5 mmol),
pyridinium salt 3 (2.5 mmol), and pyridine (6 ml) was
stirred under argon atmosphere at 100°С for 8 h. The
solvent was removed under reduced pressure, the residue
was purified by column chromatography (eluent CHCl3)
followed by recrystallization.
trans-2-Benzoyl-5-benzyl-6-methyl-3-phenyl-3,5-di-
hydrofuro[3,2-c]pyridin-4(2H)-one (4a). Yield 240 mg
(57%), colorless crystals, mp 131–132°С (MeOH). 1H NMR
spectrum, δ, ppm (J, Hz): 2.30 (3H, s, CH3); 4.77 (1H, d,
J = 4.4, 3-CH); 5.05 (1H, d, J = 15.5, CH2); 5.39 (1H, d,
J = 15.5, CH2); 5.99 (1H, d, J = 4.4, 2-CH); 6.15 (1H, s,
H-7); 7.06 (2H, d, J = 7.1, H Ar); 7.18−7.38 (8H, m, H Ar);
7.43−7.48 (2H, m, H Ar); 7.61 (1H, t, J = 7.4, H Ar); 7.85
(2H, d, J = 7.3, H Ar). 13C NMR spectrum, δ, ppm: 21.6
(CH3); 47.0 (CH2); 49.9 (3-CH); 92.1 (2-CH); 96.2 (7-CH);
109.6 (C-3a); 126.6 (2CH); 127.4 (CH); 127.7 (2CH);
128.9 (2CH); 129.0 (2CH); 129.1 (3CH); 129.2 (2CH);
133.4; 134.2 (CH); 136.6; 141.0; 149.9 (C-6); 161.0 (C-4);
167.2 (C-7a); 193.4 (C=O). Found, %: C 79.87; H 5.45;
N 3.23. C28H23NO3. Calculated, %: C 79.79; H 5.50; N 3.32.
When dimethyl phenacyl sulfonium bromide was used
instead of pyridinium salt 3, the yield of compound 4b was
50%.
trans-2-Benzoyl-5-benzyl-3-(4-chlorophenyl)-6-methyl-
3,5-dihydrofuro[3,2-с]pyridin-4(2H)-one (4b). Yield
350 g (77%), colorless crystals, mp 160–161°С (EtOH).
1H NMR spectrum, δ, ppm (J, Hz): 2.29 (3H, s, CH3); 4.69
(1H, d, J = 4.6, 3-CH); 5.03 (1H, d, J = 15.8, CH2); 5.39
(1H, d, J = 15.8, CH2); 5.92 (1H, d, J = 4.6, 2-CH); 6.09
(1H, s, H-7); 7.07 (2H, d, J = 7.6, H Ar); 7.18−7.28 (5H,
m, H Ar); 7.32 (2H, d, J = 8.2, H Ar); 7.44−7.48 (2H, m,
H Ar); 7.59−7.64 (1H, m, H Ar); 7.84 (2H, d, J = 8.2,
H Ar). 13C NMR spectrum, δ, ppm: 21.5 (CH3); 46.7
(CH2); 49.3 (3-CH); 91.7 (2-CH); 95.6 (7-CH); 108.9
(C-3a); 126.5 (2CH); 127.4 (CH); 129.0 (6CH); 129.1
(2CH); 129.3 (2CH); 133.5 (2CH); 134.3 (CH); 136.7;
139.7; 150.0 (C-6); 161.0 (C-4); 166.9 (C-7a); 193.3
(C=O). Found, %: C 73.80; H 4.81; N 2.97. C28H22ClNO3.
Calculated, %: C 73.76; H 4.86; N 3.07.
trans-2-Benzoyl-5-benzyl-3-(4-methoxyphenyl)-6-me-
thyl-3,5-dihydrofuro[3,2-c]pyridin-4(2H)-one (4c). Yield
290 mg (64%), colorless crystals, mp 155–156°С (PhMe).
1H NMR spectrum, δ, ppm (J, Hz): 2.28 (3H, s, CH3); 3.79
(3H, s, CH3O); 4.65 (1H, d, J = 4.5, 3-СH); 5.01 (1H, d,
J = 15.6, CH2); 5.40 (1H, d, J = 15.6, CH2); 5.96 (1H, d,
J = 4.5, 2-CH); 6.11 (1H, s, H-7); 6.88 (2H, d, J = 8.0,
H-3,5 4-CH3OC6H4); 7.06 (2H, d, J = 8.0, H-2,6
4-CH3OC6H4); 7.18−7.27 (5H, m, H Ph); 7.43−7.47 (2H,
m, H-3,5 C6H4С=О); 7.61 (1H, t, J = 7.4, H-4 C6H4С=О);
7.84 (2H, d, J = 7.8, H-2,6 C6H4С=О). 13C NMR spectrum,
δ, ppm: 21.5 (CH3); 46.8 (CH2); 49.4 (3-CH); 55.4 (CH3O);
92.1 (2-CH); 95.8 (7-CH); 109.6 (C-3a); 114.5 (3,5-CH
4-CH3OC6H4); 126.6 (2,6-CH 4-CH3OC6H4); 127.3 (CH
Ph); 128.7 (2CH Ph); 128.8 (2CH Ph); 128.9 (3,5-CH
C6H4С=О); 129.1 (2,6-CH C6H4С=О); 133.2 (C-1
4-CH3OC6H4); 133.4 (C–C=O); 134.1 (4-CH C6H4С=О);
136.7 (C–CH2); 149.7 (C-6); 159.1 (C–OMe); 161.1 (C-4);
166.8 (C-7a); 193.6 (C=O). Found, %: C 77.07; H 5.55;
N 3.21. C29H25NO4. Calculated, %: C 77.14; H 5.58;
N 3.10.
trans-2-Benzoyl-5-(4-methoxybenzyl)-6-methyl-3-phe-
nyl-3,5-dihydrofuro[3,2-c]pyridin-4(2H)-one (4d). Yield
293 mg (65%), colorless crystals, mp 157–158°С (PhMe).
1H NMR spectrum, δ, ppm (J, Hz): 2.31 (3H, s, CH3); 3.75
(3H, s, CH3O); 4.68 (1H, d, J = 4.3, 3-CH); 4.94 (1H, d,
J = 15.3, CH2); 5.33 (1H, d, J = 15.3, CH2); 5.97 (1H, d,
J = 4.3, 2-CH); 6.08 (1H, s, H-7); 6.78 (2H, d, J = 8.2,
H Ar); 7.03 (2H, d, J = 8.2, H Ar); 7.24−7.38 (5H, m,
H Ar); 7.45 (2H, t, J = 7.6, H Ar); 7.60 (1H, t, J = 7.3,
H Ar); 7.84 (2H, d, J = 7.8, H Ar). 13C NMR spectrum,
δ, ppm: 21.5 (CH3); 46.2 (CH2); 50.0 (3-CH); 55.3 (CH3O);
91.9 (2-CH); 95.5 (7-CH); 109.3 (C-3a); 114.2 (2CH);
127.6 (2CH); 127.7 (CH); 128.1 (2CH); 128.9 (2CH, C);
129.1 (4CH); 133.5; 134.1 (CH); 141.2; 149.7 (C-6);
158.9; 161.1 (C-4); 166.8 (C-7a); 193.6 (C=O). Found, %:
C 77.23; H 5.56; N 3.01. C29H25NO4. Calculated, %:
C 77.14; H 5.58; N 3.10.
trans-5-Benzyl-6-methyl-3-phenyl-2-(3,4,5-trimethoxy-
benzoyl)-3,5-dihydrofuro[3,2-c]pyridin-4(2H)-one (4e).
Yield 358 mg (70%), colorless crystals, mp 188–190°С
1
When the reaction was carried out in the presence of
atmospheric oxygen, furo[3,2-c]pyridin-4(5H)-one 5, yield
145 mg (32%), followed by compound 4b, yield 182 mg
(40%), were isolated by column chromatography (eluent
CHCl3).
2-Benzoyl-5-benzyl-3-(4-chlorophenyl)-6-methylfuro-
[3,2-c]pyridin-4(5H)-one (5). Yield 145 mg (32%), yellow
crystals, mp 150–151°С. 1H NMR spectrum, δ, ppm (J, Hz):
2.41 (3H, s, CH3); 5.37 (2H, br. s, CH2); 6.49 (1H, s, H-7);
7.10 (2H, d, J = 7.3, H Ar); 7.20−7.32 (7H, m, H Ar); 7.41
(2H, d, J = 8.5, H Ar); 7.47 (1H, t, J = 7.5, H Ar); 7.73
(EtOH). H NMR spectrum, δ, ppm (J, Hz): 2.30 (3H, s,
CH3); 3.69 (6H, s, CH3O); 3.91 (3H, s, CH3O); 4.70 (1H, d,
J = 4.8, 3-CH); 5.01 (1H, d, J = 15.6, CH2); 5.41 (1H, d,
J = 15.6, CH2); 6.01 (1H, d, J = 4.8, 2-CH); 6.14 (1H, s,
H-7); 7.02 (2H, s, H Ar); 7.05 (2H, d, J = 7.1, H Ar);
7.17−7.30 (4H, m, H Ar); 7.33−7.38 (4H, m, H Ar).
13C NMR spectrum, δ, ppm: 21.5 (CH3); 46.9 (CH2); 50.7
(3-CH); 56.1 (2CH3O); 61.1 (CH3O); 92.0 (2-CH); 96.1
(7-CH); 106.3 (2CH); 109.4 (C-3a); 126.5 (2CH); 127.4
(CH); 127.9 (3CH); 128.3; 128.8 (2CH); 129.2 (2CH);
136.6; 141.1; 143.3; 149.9 (C-6); 153.3 (2C); 161.0 (C-4);
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Chemistry of Heterocyclic Compounds 2020, 56(11), 1423–1428
167.1 (C-7a); 192.3 (C=O). Found, %: C 72.70; H 5.85;
trans-2-(Adamantane-1-carbonyl)-5-(4-methoxyben-
zyl)-3-(4-methoxyphenyl)-6-methyl-3,5-dihydrofuro[3,2-c]-
pyridin-4(2H)-one (4i). Yield 335 mg (62%), colorless
crystals, mp 183–184°С (EtOH). 1H NMR spectrum, δ, ppm
(J, Hz): 1.62−1.81 (9H, m, СH2 Ad); 1.87−1.93 (3H, m,
СH2 Ad); 2.02 (3H, br. s, СH Ad); 2.29 (3H, s, CH3); 3.74
(3H, s, CH3O); 3.77 (3H, s, CH3O); 4.56 (1H, d, J = 4.4,
3-CH); 4.94 (1H, d, J = 15.3, CH2); 5.32 (1H, d, J = 15.3,
CH2); 5.47 (1H, d, J = 4.4, 2-CH); 6.03 (1H, s, H-7); 6.78
(2H, d, J = 8.5, H Ar); 6.85 (2H, d, J = 8.5, H Ar); 7.02
(2H, d, J = 8.5, H Ar); 7.23 (2H, d, J = 8.5, H Ar).
13C NMR spectrum, δ, ppm: 21.5 (CH3); 27.7 (3CH Ad);
36.4 (3CH2 Ad); 38.1 (3CH2 Ad); 45.7 (C Ad); 46.5
(CH2N); 48.8 (3-CH); 55.3 (CH3O); 55.4 (CH3O); 90.1
(2-CH); 96.0 (7-CH); 110.0 (C-3a); 114.2 (2CH); 114.4
(2CH); 128.1 (2CH); 128.6 (2CH); 128.7; 133.4; 149.6
(C-6); 158.9 (2C); 161.0 (C-4); 167.1 (C-7a); 208.0 (C=O).
Found, %: C 75.72; H 6.86; N 2.52. C34H37NO5.
Calculated, %: C 75.67; H 6.91; N 2.60.
N 2.67. C31H29NO6. Calculated, %: C 72.78; H 5.71; N 2.74.
trans-2-Benzoyl-5-(3,4-dimethoxyphenethyl)-6-methyl-
3-(2-nitrophenyl)-3,5-dihydrofuro[3,2-с]pyridin-(2H)-one
(4f). Yield 405 mg (75%), colorless crystals, mp 185–186°С.
1H NMR spectrum, δ, ppm (J, Hz): 2.15 (3H, s, CH3); 2.89
(2H, br. s, CH2); 3.79 (3H, s, CH3O); 3.84 (3H, s, CH3O);
3.98−4.05 (1H, m, CH2N); 4.22−4.28 (1H, m, CH2N); 5.60
(1H, d, J = 4.1, 3-CH); 5.90 (1H, s, H-7); 5.98 (1H, d,
J = 4.1, 2-CH); 6.62 (1H, s, H Ar); 6.71 (1H, d,
J = 8.2, H Ar); 6.77 (1H, d, J = 8.2, H Ar); 7.31 (1H, d,
J = 7.1, H Ar); 7.40−7.50 (3H, m, H Ar); 7.56−7.63 (2H,
m, H Ar); 7.92 (1H, d, J = 7.8, H Ar); 7.99 (2H, d, J = 8.0,
H Ar). 13C NMR spectrum, δ, ppm: 21.4 (CH3); 34.4
(CH2); 44.2 (3-CH); 46.4 (CH2N); 56.0 (2CH3O); 89.5
(2-CH); 95.3 (7-CH); 107.3 (C-3a); 111.4 (CH); 112.2
(CH); 120.8 (CH); 125.2 (CH); 128.5 (CH); 128.9 (2CH);
129.3 (2CH); 130.3 (CH); 131.0; 133.7 (CH); 134.0 (CH);
134.6; 135.3; 147.9; 149.1 (2C); 149.7 (С-6); 160.5 (C-4);
167.3 (C-7a); 192.0 (C=O). Found, %: C 68.95; H 5.19;
N 5.09. C31H28N2O7. Calculated, %: C 68.88; H 5.22; N 5.18.
trans-2-Benzoyl-6-methyl-3-phenyl-5-(pyridin-3-yl-
methyl)-3,5-dihydrofuro[3,2-c]pyridin-4(2H)-one (4g).
Yield 367 mg (68%), colorless crystals, mp 159–160°С
(2'R*,3'R*)-5'-Benzyl-6'-methyl-3'-phenyl-3',5'-dihydro-
4'H-spiro[indene-2,2'-furo[3,2-c]pyridine]-1,4'(3H)-dione
(4j). Yield 234 mg (54%), colorless crystals, mp 170–172°С
1
(EtOH). H NMR spectrum, δ, ppm (J, Hz): 2.32 (3H, s,
CH3); 2.86 (1H, d, J = 17.4, CH2); 3.10 (1H, d,
J = 17.4, CH2); 4.84 (1H, s, 3'-CH); 5.23 (1H, d, J = 15.7,
CH2N); 5.35 (1H, d, J = 15.7, CH2N); 6.05 (1H, s, H-7');
7.01 (2H, d, J = 6.7, H Ar); 7.11 (2H, d, J = 7.3, H Ar);
7.20−7.31 (7H, m, H Ar); 7.42 (1H, t, J = 7.4, H Ar); 7.58
(1H, t, J = 7.4, H Ar); 7.84 (1H, d, J = 7.8, H Ar).
13C NMR spectrum, δ, ppm: 21.5 (CH3); 36.0 (CH2); 47.1
(CH2N); 51.2 (3'-CH); 96.0 (C-2'); 96.3 (7'-CH); 109.9
(C-3a'); 125.5 (2CH); 126.4 (CH); 126.6 (2CH); 127.4
(CH); 127.8 (CH); 128.4 (CH); 128.6 (CH); 128.9 (4CH);
133.4; 136.1 (CH); 136.6; 138.0; 149.7 (C-6'); 150.6; 160.9
(C-4'); 167.3 (C-7a'); 200.6 (C=O). Found, %: C 80.37;
H 5.40; N 3.18. C29H23NO3. Calculated, %: C 80.35;
H 5.35; N 3.23.
1
(EtOH). H NMR spectrum, δ, ppm (J, Hz): 2.30 (3H, s,
CH3); 4.67 (1H, d, J = 4.6, 3-CH); 5.07 (1H, d, J = 15.9,
CH2); 5.34 (1H, d, J = 15.9, CH2); 5.98 (1H, d, J = 4.6,
2-CH); 6.12 (1H, s, H-7); 7.21−7.30 (4H, m, H Ar);
7.33−7.37 (2H, m, H Ar); 7.42−7.53 (3H, m, H Ar); 7.60
(1H, t, J = 7.5, H Ar); 7.84 (2H, d, J = 8.2, H Ar);
8.44−8.48 (2H, m, H Ar). 13C NMR spectrum, δ, ppm: 21.5
(CH3); 44.5 (CH2); 49.8 (3-CH); 91.9 (2-CH); 96.1 (7-CH);
109.5 (C-3a); 124.1 (CH); 127.6 (CH); 127.8 (CH); 129.0
(2CH); 129.1 (3CH); 129.2 (2CH); 133.0; 133.4; 134.2
(CH); 135.6 (CH); 140.9; 147.6 (CH); 148.2 (CH); 149.1
(C-6); 161.0 (C-4); 167.1 (C-7a); 193.4 (C=O). Found, %:
C 76.83; H 5.19; N 6.59. C27H22N2O3. Calculated, %:
C 76.76; H 5.25; N 6.63.
trans-2-Benzoyl-3-(4-chlorophenyl)-6-methyl-2,3-di-
hydro-4H-furo[3,2-c]pyran-4-one (6). A mixture of
4-hydroxy-6-methyl-2H-pyran-2-one (315 mg, 2.5 mmol),
4-methoxybenzylamine (345 mg, 2.5 mmol), 4-chlorobenz-
aldehyde (350 mg, 2.5 mmol), phenacyl pyridinium
bromide (695 mg, 2.5 mmol), and pyridine (10 ml) was
heated with stirring under argon atmosphere at 100°С for 8 h.
The solvent was removed under reduced pressure, and the
residue was purified by column chromatography (eluent
CHCl3), followed by recrystallization from EtOH. Yield
410 mg (45%), colorless crystals, mp 148–149°С (mp 145–
147°С12). The spectral characteristics of compound 6
correspond to those described in the literature.12
trans-2-(Adamantane-1-carbonyl)-3-(4-chlorophenyl)-
5-(4-methoxybenzyl)-6-methyl-3,5-dihydrofuro[3,2-c]-
pyridin-4(2H)-one (4h). Yield 430 mg (79%), colorless
crystals, mp 182–183°С (EtOH). 1H NMR spectrum, δ, ppm
(J, Hz): 1.64−1.80 (9H, m, CH2 Ad); 1.87−1.91 (3H, m,
CH2 Ad); 2.02 (3H, br. s, CH Ad); 2.29 (3H, s, CH3); 3.74
(3H, s, CH3O); 4.55 (1H, d, J = 4.6, 3-CH); 4.94 (1H, d,
J = 15.2, CH2); 5.32 (1H, d, J = 15.2, CH2); 5.43 (1H, d,
J = 4.6, 2-CH); 6.00 (1H, s, H-7); 6.78 (2H, d, J = 8.7,
H-3,5 4-CH3OC6H4); 7.02 (2H, d, J = 8.5, H-2,6
4-CH3OC6H4); 7.23 (2H, d, J = 8.7, H-2,6 4-ClC6H4); 7.29
(2H, d, J = 8.5, H-3,5 4-ClC6H4). 13C NMR spectrum,
δ, ppm: 21.5 (CH3); 27.7 (3CH Ad); 36.4 (3CH2 Ad); 38.0
(3CH2 Ad); 45.8 (C Ad); 46.3 (CH2N); 48.9 (3-CH); 55.4
(CH3O); 89.7 (2-CH); 95.6 (7-CH); 109.3 (C-3a); 114.2
(3,5-CH 4-CH3OC6H4); 128.1 (2,6-CH 4-CH3OC6H4);
128.7 (C-1 4-CH3OC6H4); 129.0 (2,6-CH 4-ClC6H4); 129.1
(3,5-CH 4-ClC6H4); 133.2 (C–Cl); 139.9 (C-1 4-ClC6H4);
149.9 (C-6); 158.9 (C–OMe); 161.0 (C-4); 167.0 (C-7a);
207.8 (C=O). Found, %: C 72.92; H 6.28; N 2.49.
C33H34ClNO4. Calculated, %: C 72.85; H 6.30; N 2.57.
The study was carried out with the financial support of
the Russian Foundation for Basic Research within the
framework of the research project 19-03-01024.
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