Synthesis of 1-aryl-2-[2-(dimethylamino)ethyl]-1,2-dihydrochromeno[2,3-c] pyrrole-3,9-diones and their analogs

Article abstract of DOI:10.1134/S1070363210020222

Methyl o-hydroxybenzoylpyruvate heated with N,N-dimethylethylenediamine and aromatic aldehydes affords in a high yield 5-aryl-3-hydroxy-4-(2-hydroxyphenyl) -1-[2-(dimethylamino)ethyl]-1,5-dihydro-2H-pyrrol-2-ones, which easily split off water at boiling in acetic acid and are converted into 1-aryl-2-[(2- dimethylamino)ethyl]-1,2-dihydrochromeno[2,3-c]pyrrol-3,9-diones. The developed route of synthesis provides a wide range of derivatives of 1-aryl-2-[ω- (dialkylamino)alkyl]-1,2-dihydrochromeno[2,3-c]pyrrole-3,9-diones.

Full text of DOI:10.1134/S1070363210020222

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 2, pp. 323–329. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © R.N. Vydzhak, S.Ya. Panchishyn, 2010, published in Zhurnal Obshchei Khimii, 2010, Vol. 80, No. 2, pp. 298–304.
Synthesis of 1-Aryl-2-[2-(dimethylamino)ethyl]-1,2-
dihydrochromeno[2,3-c]pyrrole-3,9-diones
and Their Analogs
R. N. Vydzhak and S. Ya. Panchishyn
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kiev, 02660 Ukraine
e-mail: vydzhak@mail.ru
Received May 5, 2009
Abstract―Methyl o-hydroxybenzoylpyruvate heated with N,N-dimethylethylenediamine and aromatic
aldehydes affords in a high yield 5-aryl-3-hydroxy-4-(2-hydroxyphenyl)-1-[2-(dimethylamino)ethyl]-1,5-
dihydro-2H-pyrrol-2-ones, which easily split off water at boiling in acetic acid and are converted into 1-aryl-2-
[(2-dimethylamino)ethyl]-1,2-dihydrochromeno[2,3-c]pyrrol-3,9-diones. The developed route of synthesis
provides a wide range of derivatives of 1-aryl-2-[ω-(dialkylamino)alkyl]-1,2-dihydrochromeno[2,3-c]pyrrole-
3,9-diones.
DOI: 10.1134/S1070363210020222
It was shown previously that a reaction of methyl o-
hydroxybenzoylpyruvate with a mixture of aromatic
aldehyde and heterylamine [1] or with a Schiff base [2]
leds to 1-aryl-2-heteryl- or 1,2-diaryl-1,2-dihydro-
chromeno[2,3-c]pyrrole-3,9-diones, respectively. It is
also known that the reactions of acylpyruvate esters
with a mixture of aromatic aldehyde and N,N-
dimethylethylenediamine [3] or N,N-diethylethylene-
diamine [4] leads to 5-aryl-4-acyl-3-hydroxy-1-(N,N-
dialkylaminoethyl)-1,5-dihydro-2H-pyrrol-2-ones. Such
pyrrole derivatives are pharmacologically active
compounds with various type of activity [3–6]. The
activity of 2-aryl(hetero)-1,2-dihydrochromeno[2,3-c]-
pyrrol-3 ,9-diones without substituents in position 1
was studied [7], and it was stated that 2-(3-morpholin-
4-yl-propyl)-1-phenyl-1,2-dihydrochromeno[2,3-c]-
pyrrole-3 ,9-dione exhibited antitumor activity, being
an inhibitor of Hsp90 [8]. Taking into account that
some of the drugs used in medical practice contain ω-
dialkylaminoalkyl group [9], we found it interesting to
OH
O
O
O
Ar
N(CH2)nNR2
OMe
O
H
IIa_IIe
+
Ar
+ H2N(CH2)nNR2
O
OH
OH
VIII_XII
O
III_VII
I
O
O
O
Ar
Ar
N(CH2)nNR2
CH3COOH
NaOH
N(CH2)nNR2 CH3COOH
O
O
O
XIII_XVII
A
Ar = C6H5 (a), 4-ClC6H4 (b), 4-O2NC6H4 (c), 4-CH3OC6H4 (d), 3,4-(CH3O)2C6H3 (e); R2N = (CH3)2N (III, VI, VIIIa–VIIIe, XIa–XIe,
XIIIa–XIIIe, XVIa–XVIe), (C2H5)2N (IV, IXa, IXd, XIVa, XIVd), O(CH2CH2)2N (V, VII, Xa, Xb, Xe, XIIa, XIId, XIIe, XVa, XVb,
XVe, XVIIa, XVIId, XVIIe); n = 2 (III–V, VIII–X, XIII–XV), 3 (VI, VII, XI, XII, XVI, XVII).
323

324
VYDZHAK, PANCHISHYN
search for an approach to the synthesis of 2-(ω-
dialkylaminoalkyl)-1,2-dihydrochromeno[2,3-c]-
pyrrole-3,9-diones. In order to obtain such functionally
substituted fused heterocyclic compounds we studied
the transformation of methyl o-hydroxybenzoyl-
pyruvate into substituted pyrrolones and cyclization of
the latter into 1,2-dihydrochromeno[2,3-c]pyrrole-3,9-
diones (see the scheme).
method of formation of pyran ring is often used in the
synthesis of heteropyrones [10, 11] and the chromone
fused derivatives [12]. It was unnecessary to isolate the
substituted pyrroles VIII–XII in an individual state.
To methanolic suspension of a compound VIII–XII
was added acetic acid and the reaction mixture was
refluxed for 1 h. This approach can be used as a
convenient one-pot method of synthesis. Its dis-
advantage is the large amount of impurities in the final
product, which makes its purification slightly more
difficult. Substituents at the nucleus of the aromatic
aldehyde affect the yield of products XIII–XVII: The
electron-acceptors increase the yield of chromeno-
pyrroles, while electron-donors reduce it.
At heating equimolar amounts of ester I, aromatic
aldehyde II, and substituted aliphatic amine III–VII in
methanol formed pyrrolones VIII–XII in a good yield.
Their structure is doubtless, because such compounds
are described in the literature [3, 4]. Their composition
is confirmed by elemental analysis, and structure, by
1
IR and H NMR spectroscopy. The obtained com-
The structure of the synthesized compounds was
confirmed by IR and 1H NMR spectroscopy (Table 1),
and their composition, by the data of elemental
analysis (Table 2). The IR spectra of 1,2-dihydro-
chromeno[2,3-c]pyrrole-3,9-diones, taken from the
tablets with KBr, contain in the region of 1590–
1720 cm–1 three characteristic absorption bands: 1600–
1620 cm–1 (moderate intensity band of C=C stretching
vibrations), 1640–1665 cm–1 (strong band of stretching
vibrations of the C9=O), and 1695–1720 cm–1 (strong
band of C3=O stretching vibrations). The relative
pound VIII–XII are lemon-yellow crystalline
substances, sparingly soluble in alcohol, dioxane and
ethyl acetate, but readily soluble in acetic acid and
aqueous solutions of acids and bases. When heated in
acetic acid, hydroxypyrrolones VIII–XII undergo
dehydration with the formation of 1,2-dihydro-
chromeno[2,3-c]pyrrol-3,9-diones, which exist in
solution in the form of acetates (A). By treating them
with a solution of sodium hydroxide we obtained
substituted chromone free bases XIII–XVII. This
Table 1. Spectral characteristics of compounds VIII–XVII
Comp. IR spectrum (KBr),
1Н NMR spectrum, δ, ppm
no.
ν, cm–1
VIIIаа
2.72–2.86 m [7Н, НC NCH2, N(CH3)2], 2.97 m (1H, HB CH2NMe2), 3.24 m (1H, HA CH2NMe2), 3.83 m
1606 (С=С); 1616
(C=O ketone); 1687
(C2=O); 3429 (OH)
3
3
3
(1H, HA NCH2), 5.42 s (1H, C5-H), 6.64 d (1H, JHH 8.4 Hz, С3'-H), 6.74 d.d (1H, JHH 7.8, JHH 8.1 Hz,
C5'-H), 7.16–7.31 m (6Н, C4'-H, 5Н arom.), 8.61 d (1H, 3JHH 7.8 Hz, С6'-H), 13.35 s (1Н, ОН)
2.75–2.91 m [7Н, НC NCH2, N(CH3)2], 3.00 m (1H, HB CH2NMe2), 3.27 m (1H, HA CH2NMe2), 3.83 m
(1H, HA NCH2), 5.47 s (1H, C5-H), 6.64 d (1H, С3'-H), 6.74 d.d (1H, C5'-H), 7.14–7.33 m (5Н, C4'-H, 4Н
arom.), 8.62 d (1H, С6'-H), 13.37 s (1Н, ОН)
VIIIb
VIIIcа
1605 (С=С); 1618
(C=O ketone); 1691
(C2=O); 3430 (OH)
2.69–2.84 m [7Н, НC NCH2, N(CH3)2], 3.02 m (1H, HB CH2NMe2), 3.38 m (1H, HA CH2NMe2), 3.94 m
1607 (С=С); 1619
(C=O ketone); 1699
(C2=O); 3427 (OH)
3
3
3
(1H, HA NCH2), 5.54 s (1H, C5-H), 6.64 d (1H, JHH 8.4 Hz, С3'-H), 6.74 d.d (1H, JHH 7.8, JHH 8.1 Hz,
C5'-H), 7.22 d.d (1H, 3JHH 8.1, 3JHH 8.4 Hz, C4'-H), 7.57 d (2Н arom.), 8.11 d (2Н arom.), 8.61 d (1H, 3JHH
7.8 Hz, С6'-H), 9.55 s (1Н, ОН), 13.67 s (1Н, ОН)
2.70–2.86 m [7Н, НC NCH2, N(CH3)2], 2.97 m (1H, HB CH2NMe2), 3.27 m (1H, HA CH2NMe2), 3.67–3.87
m (4H, HA NCH2, СН3О), 5.36 s (1H, C5-H), 6.63 d (1H, С3'-H), 6.70–6.79 m (3H, C5'-H, 2Н arom.), 7.16–
7.28 m (3Н, C4'-H, 2Н arom.), 8.58 d (1H, С6'-H)
VIIId
VIIIe
IXа
1605 (С=С); 1610
(C=O ketone); 1689
(C2=O); 3432 (OH)
2.70–2.85 m [7Н, НC NCH2, N(CH3)2], 2.96 m (1H, HB CH2NMe2), 3.27 m (1H, HA CH2NMe2), 3.67–3.84
m (7H, HA NCH2, 2 СН3О), 5.36 s (1H, C5-H), 6.63–6.89 m (5Н, С3'-H, C5'-H, 3Н arom.), 7.22 d.d (1H,
C4'-H), 8.61 d (1H, С6'-H)
1600 (С=С); 1618
(C=O ketone); 1698
(C2=O); 3428 (OH)
1.12 т (6Н, 2СН3), 2.88 m (1Н, НC NCH2), 2.97–3.18 m (6Н, 3 NCH2), 3.78 m (1H, HA NCH2), 5.39 s
(1H, C5-H), 6.64 d (1H, С3'-H), 6.77 d.d (1H, C5'-H), 7.16–7.31 m (6Н, C4'-H, 5Н arom.), 8.62 d (1H, С6'-
H), 13.44 s (1Н, ОН)
1605 (С=С); 1617
(C=O ketone); 1688
(C2=O); 3430 (OH)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 2 2010

SYNTHESIS OF 1-ARYL-2-[2-(DIMETHYLAMINO)ETHYL]-1,2-...
325
Table 1. (Contd.)
Comp.
no.
IR spectrum (KBr),
ν, cm–1
1Н NMR spectrum, δ, ppm
IXd
1605 (С=С); 1614 (C=O 1.12 т (6Н, 2СН3), 2.89 m (1Н, НC NCH2), 2.96–3.18 m (6Н, 3 NCH2), 3.69 s (3H, CH3O), 3.79 m (1H,
ketone); 1689 (C2=O); HA NCH2), 5.37 s (1H, C5-H), 6.63 d (1H, С3'-H), 6.69–6.79 m (3H, C5'-H, 2Н arom.), 7.15–7.29 m (3Н,
3432 (OH)
C4'-H, 2Н arom.), 8.59 d (1H, С6'-H)
Xа
1606 (С=С); 1615 (C=O 2.42–2.52 m (6Н, 3NCH2), 2.79 m (1Н, НC NCH2), 3.52–3.62 m (4Н, 2OCH2), 3.78 m (1Н, HA NCH2),
ketone); 1682 (C2=O); 5.43 s (1H, C5-H), 6.64 d (1H, С3'-H), 6.75 d.d (1H, C5'-H), 7.16–7.32 m (6Н, C4'-H, 5Н arom.), 8.61 d
3429 (OH)
(1H, С6'-H)
Xb
1605 (С=С); 1614 (C=O 2.42–2.52 m (6Н, 3NCH2), 2.79 m (1Н, НC NCH2), 3.52–3.62 m (4Н, 2OCH2), 3.79 m (1Н, HA NCH2),
ketone); 1683 (C2=O); 5.45 s (1H, C5-H), ), 6.63 d (1H, С3'-H), 6.74 d.d (1H, C5'-H), 7.13–7.33 m (5Н, C4'-H, 4Н arom.), 8.63 d
3432 (OH)
(1H, С6'-H)
Xe
1605 (С=С); 1617 (C=O 2.41–2.52 m (6Н, 3NCH2), 2.79 m (1Н, НC NCH2), 3.55–3.62 m (4Н, 2OCH2), 3.68–3.81 m (7Н, HA
ketone); 1688 (C2=O); NCH2, 2 СН3О), 5.46 s (1H, C5-H), 6.63–6.89 m (5Н, С3'-H, C5'-H, 3Н arom.), 7.22 d.d (1H, C4'-H),
3430 (OH)
8.61 d (1H, С6'-H)
XIа
XIb
XIc
XId
XIe
XIIа
XIId
1604 (С=С); 1617 (C=O 1.68–1.82 m (2Н, СН2), 2.61–2.82 m [7Н, НC NCH2, N(CH3)2], 2.83–2.93 m (2Н, CH2NMe2), 3.49 m
ketone); 1687 (C2=O); (1H, HA NCH2), 5.31 s (1H, C5-H), 6.64 d (1H, С3'-H), 6.71 d.d (1H, C5'-H), 7.15–7.34 m (6Н, C4'-H, 5Н
3430 (OH)
arom.),8.68 d (1H, С6'-H)
1605 (С=С); 1619 (C=O 1.74–1.86 m (2Н, СН2), 2.59–2.76 m [7Н, НC NCH2, N(CH3)2], 2.88–2.97 m (2Н, CH2NMe2), 3.52 m
ketone); 1684 (C2=O); (1H, HA NCH2), 5.33 s (1H, C5-H), 6.65 d (1H, С3'-H), 6.71 d.d (1H, C5'-H), 7.17–7.33 m (5Н, C4'-H, 4Н
3430 (OH)
arom.), 8.68 d (1H, С6'-H)
1605 (С=С); 1617 (C=O 1.74–1.86 m (2Н, СН2), 2.59–2.76 m [7Н, НC NCH2, N(CH3)2], 2.88–2.97 m (2Н, CH2NMe2), 3.52 m
ketone); 1685 (C2=O); (1H, HA NCH2), 5.52 s (1H, C5-H), 6.64 d (1H, С3'-H), 6.74 d.d (1H, C5'-H), 7.22 d.d (1H, C4'-H), 7.57 d
3428 (OH)
(2Н arom.), 8.11 d (2Н arom.), 8.61 d (1H, С6'-H)
1600 (С=С); 1611 (C=O 1.69–1.82 m (2Н, СН2), 2.62–2.82 m [7Н, НC NCH2, N(CH3)2], 2.84–2.95 m (2Н, CH2NMe2), 3.49 m
ketone); 1689 (C2=O); (1H, HA NCH2), 3.69 s (3H, CH3O), 5.29 s (1H, C5-H), 6.30–6.86 m (4H, С3'-H, C5'-H, 2Н arom.), 7.15–
3422 (OH)
7.28 m (3Н, C4'-H, 2Н arom.), 8.68 d (1H, С6'-H), 10.37 s (1Н, ОН), 13.77 s (1Н, ОН)
1604 (С=С); 1616 (C=O 1.69–1.82 m (2Н, СН2), 2.62–2.81 m [7Н, НC NCH2, N(CH3)2], 2.83–2.95 m (2Н, CH2NMe2), 3.49 m
ketone); 1683 (C2=O); (1H, HA NCH2), 3.69 s (3H, CH3O), 3.76 s (3H, CH3O), 5.31 s (1H, C5-H), 6.63–6.89 m (5Н, С3'-H, C5'-
3426 (OH)
H, 3Н arom.), 7.22 d.d (1H, C4'-H), 8.61 d (1H, С6'-H)
1604 (С=С); 1616 (C=O 1.67–1.91 m (2Н, СН2), 2.64 m (1Н, НC NCH2), 2.74–3.05 m (6Н, 3NCH2), 3.49 m (1Н, HA NCH2),
ketone); 1689 (C2=O); 3.75–3.87 m (4Н, 2OCH2), 5.36 s (1H, C5-H), 6.66–6.76 m (2Н, С3'-H, C5'-H), 7.17–7.33 m (6Н, C4'-H,
3435 (OH)
5Н arom.), 8.37 d (1H, С6'-H)
1603 (С=С); 1614 (C=O 1.66–1.92 m (2Н, СН2), 2.61 m (1Н, НC NCH2), 2.74–3.05 m (6Н, 3NCH2), 3.52 m (1Н, HA NCH2),
ketone); 1679 (C2=O); 3.69 s (3H, CH3O), 3.75–3.87 m (4Н, 2OCH2), 5.36 s (1H, C5-H), 6.62–6.81 m (4Н, С3'-H, C5'-H, 2Н
3440 (OH)
arom), 7.16–7.29 m (3Н, C4'-H, 2Н arom.), 8.37 d (1H, С6'-H)
XIIe
1604 (С=С); 1616 (C=O 1.66–1.92 m (2Н, СН2), 2.61 m (1Н, НC NCH2), 2.74–3.05 m (6Н, 3NCH2), 3.52 m (1Н, HA NCH2),
ketone); 1690 (C2=O); 3.64–3.87 m (10Н, 2OCH2, 2CH3O), 5.37 s (1H, C5-H), 6.63–6.89 m (5Н, С3'-H, C5'-H, 3Н arom.), 7.22
3435 (OH)
d.d (1H, C4'-H), 8.61 d (1H, С6'-H)
XIIIаb
1610 (С=С); 1660 2.14 s [6Н, N(CH3)2], 2.34–2.40 m (2Н, CH2NMe2), 2.71 m (1Н, НC NCH2), 3.84 m (1Н, HA NCH2),
3
3
(C9=O); 1718 (C3=O)
5.74 s (1Н, С1-Н), 7.31–7.40 m (5Н arom.), 7.52 d.d (1Н, JHH 7.8, JHH 8.1 Hz, С7-Н), 7.78–7.89 m
(2Н, С5-Н, С6-Н), 8.03 d (1Н, 3JHH 7.8 Hz, С8-Н)
XIIIb
1609 (С=С); 1653 2.16 s [6Н, N(CH3)2], 2.36–2.45 m (2Н, CH2NMe2), 2.78 m (1Н, НC NCH2), 3.86 m (1Н, HA NCH2),
(C9=O); 1718 (C3=O)
5.78 s (1Н, С1-Н), 7.35–7.42 m (4Н arom.), 7.52 d.d (1Н, С7-Н), 7.78–7.90 m (2Н, С5-Н, С6-Н), 8.03 d
(1Н, С8-Н)
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VYDZHAK, PANCHISHYN
Table 1. (Contd.)
Comp.
no.
IR spectrum (KBr),
ν, cm–1
1Н NMR spectrum, δ, ppm
1609 (С=С); 1652 2.17 s [6Н, N(CH3)2], 2.36–2.48 m (2Н, CH2NMe2), 2.80 m (1Н, НC NCH2), 3.91 m (1Н, HA NCH2),
XIIIc
(C9=O); 1711 (C3=O)
5.98 s (1Н, С1-Н), 7.53 d.d (1Н, С7-Н), 7.68–7.76 m (2Н arom.) 7.79–7.91 m (2Н, С5-Н, С6-Н), 8.02 d
(1Н, С8-Н), 8.18–8.25 m (2Н arom.)
1609 (С=С); 1652 2.16 s [6Н, N(CH3)2], 2.34–2.42 m (2Н, CH2NMe2), 2.79 m (1Н, НC NCH2), 3.76 s (3Н, СН3О), 3.84
XIIId
(C9=O); 1714 (C3=O)
m (1Н, HA NCH2), 5.68 s (1Н, С1-Н), 6.85–6.93 m (2Н arom.), 7.21–7.30 m (2Н arom.) 7.52 d.d (1Н,
С7-Н), 7.76–7.89 m (2Н, С5-Н, С6-Н), 8.03 d (1Н, С8-Н)
1609 (С=С); 1653 2.17 s [6Н, N(CH3)2], 2.35–2.44 m (2Н, CH2NMe2), 2.82 m (1Н, НC NCH2), 3.72 s (3Н, СН3О), 3.76
XIIIe
XIVа
XIVd
XVа
(C9=O); 1716 (C3=O)
s (3Н, СН3О), 3.85 m (1Н, HA NCH2), 5.78 s (1Н, С1-Н), 6.83–6.92 m (3Н arom.), 7.52 d.d (1Н, С7-
Н), 7.78–7.90 m (2Н, С5-Н, С6-Н), 8.04 d (1Н, С8-Н)
1609 (С=С); 1653 0.85–1.01 m (6Н, 2СН3), 2.32–2.65 m (6Н, 3NСН2), 2.83 m (1Н, НC NCH2), 3.83 m (1Н, HA NCH2),
(C9=O); 1711 (C3=O)
5.76 s (1Н, С1-Н), 7.29–7.41 m (5Н arom.), 7.52 d.d (1Н, С7-Н), 7.79–7.90 m (2Н, С5-Н, С6-Н), 8.03
d (1Н, С8-Н)
1610 (С=С); 1653 0.85–0.98 m (6Н, 2СН3), 2.34–2.64 m (6Н, 3NСН2), 2.82 m (1Н, НC NCH2), 3.64–3.78 m (4H, HA
(C9=O); 1710 (C3=O)
NCH2, СН3О), 5.70 s (1Н, С1-Н), 6.86–6.95 m (2Н arom.), 7.21–7.29 m (2Н arom.) 7.53 d.d (1Н,
С7-Н), 7.80–7.91 m (2Н, С5-Н, С6-Н), 8.03 d (1Н, С8-Н)
1610 (С=С); 1661 2.27–2.47 m (6Н, 3NCH2), 2.86 m (1Н, НC NCH2), 3.49–3.60 m (4Н, 2OCH2), 3.85 m (1Н, HA
(C9=O); 1700 (C3=O)
NCH2), 5.78 s (1Н, С1-Н), 7.32–7.39 m (5Н arom.), 7.52 d.d (1Н, С7-Н), 7.78–7.89 m (2Н, С5-Н,
С6-Н), 8.04 d (1Н, С8-Н)
1610 (С=С); 1664 2.25–2.48 m (6Н, 3NCH2), 2.85 m (1Н, НC NCH2), 3.48–3.62 m (4Н, 2OCH2), 3.86 m (1Н, HA
XVb
XVe
(C9=O); 1701 (C3=O)
NCH2), 5.81 s (1Н, С1-Н), 7.35–7.43 m (4Н arom.), 7.52 d.d (1Н, С7-Н), 7.78–7.89 m (2Н, С5-Н,
С6-Н), 8.03 d (1Н, С8-Н)
1609 (С=С); 1653 2.28–2.46 m (6Н, 3NCH2), 2.87 m (1Н, НC NCH2), 3.51–3.58 m (4Н, 2OCH2), 3.72 s (3H, CH3O),
(C9=O); 1714 (C3=O)
3.76 s (3H, CH3O), 3.83 m (1Н, HA NCH2), ), 5.69 s (1Н, С1-Н), 6.83–6.92 m (3Н arom.), 7.52 d.d
(1Н, С7-Н), 7.79–7.89 m (2Н, С5-Н, С6-Н), 8.03 d (1Н, С8-Н)
1610 (С=С); 1654 1.46–1.73 m (2Н, СН2), 2.08 s [6Н, N(CH3)2], 2.13–2.23 m (2Н, CH2NMe2), 2.86 m (1Н, НC NCH2),
XVIа
(C9=O); 1708 (C3=O)
3.65 m (1H, HA NCH2), 5.69 s (1Н, С1-Н), 7.31–7.39 m (5Н arom.), 7.52 d.d (1Н, С7-Н), 7.79–7.90 m
(2Н, С5-Н, С6-Н), 8.04 d (1Н, С8-Н)
1611 (С=С); 1663 1.49–1.74 m (2Н, СН2), 2.11 s [6Н, N(CH3)2], 2.15–2.26 m (2Н, CH2NMe2), 2.85 m (1Н, НC NCH2),
XVIb
XVIc
XVId
(C9=O); 1695 (C3=O)
3.67 m (1H, HA NCH2), 5.74 s (1Н, С1-Н), 7.35–7.42 m (4Н arom.), 7.52 d.d (1Н, С7-Н), 7.79–7.90 m
(2Н, С5-Н, С6-Н), 8.04 d (1Н, С8-Н)
1609 (С=С); 1652 1.53–1.77 m (2Н, СН2), 2.12 s [6Н, N(CH3)2], 2.19–2.30 m (2Н, CH2NMe2), 2.85 m (1Н, НC NCH2),
(C9=O); 1711 (C3=O)
3.71 m (1H, HA NCH2), 5.94 s (1Н, С1-Н), 7.53 d.d (1Н, С7-Н), 7.68–7.75 m (2Н arom.) 7.80–7.91 m
(2Н, С5-Н, С6-Н), 8.03 d (1Н, С8-Н), 8.14–8.24 m (2Н arom.)
1610 (С=С); 1654 1.48–1.74 m (2Н, СН2), 2.11 s [6Н, N(CH3)2], 2.15–2.26 m (2Н, CH2NMe2), 2.85 m (1Н, НC NCH2),
(C9=O); 1708 (C3=O)
3.63 m (1H, HA NCH2), 3.76 s (3H, CH3O), 5.63 s (1Н, С1-Н), 6.85–6.92 m (2Н arom.), 7.21–7.28 m
(2Н arom.) 7.52 d.d (1Н, С7-Н), 7.78–7.90 m (2Н, С5-Н, С6-Н), 8.04 d (1Н, С8-Н)
1610 (С=С); 1653 1.48–1.74 m (2Н, СН2), 2.10 s [6Н, N(CH3)2], 2.13–2.25 m (2Н, CH2NMe2), 2.90 m (1Н, НC NCH2),
XVIe
(C9=O); 1707 (C3=O)
3.64 m (1H, HA NCH2), 3.72 s (3H, CH3O), 3.76 s (3H, CH3O), 5.61 s (1Н, С1-Н), 6.86–6.92 m (3Н
arom.), 7.52 d.d (1Н, С7-Н), 7.77–7.89 m (2Н, С5-Н, С6-Н), 8.04 d (1Н, С8-Н)
1610 (С=С); 1663 1.50–1.79 m (2Н, СН2), 2.13–2.26 m (6Н, 3NCH2), 2.87 m (1Н, НC NCH2), 3.43–3.56 m (4H,
XVIIа
(C9=O); 1719 (C3=O)
2OCH2), 3.68 m (1H, HA NCH2), 5.70 s (1Н, С1-Н), 7.31–7.40 m (5Н arom.), 7.52 d.d (1Н, С7-Н),
7.79–7.91 m (2Н, С5-Н, С6-Н), 8.04 d (1Н, С8-Н)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 2 2010

SYNTHESIS OF 1-ARYL-2-[2-(DIMETHYLAMINO)ETHYL]-1,2-...
327
Table 1. (Contd.)
Comp.
no.
IR spectrum (KBr),
ν, cm–1
1Н NMR spectrum, δ, ppm
1609 (С=С); 1653 1.50–1.79 m (2Н, СН2), 2.14–2.39 m (6Н, 3NCH2), 2.87 m (1Н, НC NCH2), 3.47–3.55 m (4H,
XVIId
(C9=O); 1718 (C3=O)
2OCH2), 3.65 m (1H, HA NCH2), 3.76 s (3H, CH3O), 5.63 s (1Н, С1-Н), ), 6.84–6.92 m (2Н arom.),
7.21–7.29 m (2Н arom.) 7.52 d.d (1Н, С7-Н), 7.78–7.90 m (2Н, С5-Н, С6-Н), 8.04 d (1Н, С8-Н)
1608 (С=С); 1660 1.48–1.79 m (2Н, СН2), 2.14–2.39 m (6Н, 3NCH2), 2.87 m (1Н, НC NCH2), 3.47–3.68 m (5H, HA
XVIIe
(C9=O); 1711 (C3=O)
NCH2, 2OCH2), 3.72 s (3H, CH3O), 3.76 s (3H, CH3O), 5.63 s (1Н, С1-Н), 6.84–6.94 m (3Н arom.),
7.53 d.d (1Н, С7-Н), 7.77–7.89 m (2Н, С5-Н, С6-Н), 8.05 d (1Н, С8-Н)
a
Spin–spin coupling constants in the o-hydroxybenzoyl fragment of compounds VIIIa and VIIIc. The same values in all compounds
VIII–XII. b Spin–spin coupling constants C7–H and C8–H. The same values in all compounds XIII–XVII.
intensity and position of these bands depend on the
nature of the substituents, but the overall picture is
similar for all compounds. In the region of 3200–
3600 cm–1 there are no absorption bands, which
confirms the involvement of OH groups into the
cyclocondensation. In the 1H NMR spectra of
compounds XIII–XVII (Table 1) in the region of
5.30–5.80 ppm there is a singlet, which corresponds to
the signal of the hydrogen atom C1–H. The signals of
C5–H and C6–H appear as a multiplet in the region of
7.75–7.95 ppm, C7–H gives rise to a doublet of
doublets in the region of 7.50–7.60 ppm, C8–H appears
as a doublet at 8.00–8.10 ppm. The hydrogen atoms of
methylene groups in position 2 of the heterocycle are
enantiotopic, and appear as two multiplets in the
spectra of all studied compounds.
3-Hydroxy-4-(2-hydroxybenzoyl)-1-[2-(dimethyl-
amino)ethyl]-5-phenyl-1,5-dihydro-2H-pyrrol-2-one
(VIIIa). To a solution of 0.01 mol of benzaldehyde in
15 ml of anhydrous methanol was added 0.01 mol of
2-(dimethylamino)ethylamine, and the mixture was
heated to 50°C and left standing for 20 min. To the
mixture heated to 30–35°C was added 0.01 mol of
methyl o-hydroxybenzoylpyruvate, the reaction mix-
ture was heated to boiling, kept for 30 minutes at a
temperature of 35–40°C, then cooled, the precipitate
was filtered off, washed with methanol and ethyl
acetate, and then the compound VIIIa without
additional purification was used for further trans-
formations. For analysis, a sample of compound VIIIa
was purified by crystallization and dried at 85°C for
7 days.
Similarly were prepared compounds VIIIb–VIIIe,
IXa, IXe, Xa, Xb, Xe, XIa–XIe, XIIa, XIId, XIIe.
Melting points, yields and data of elemental analysis of
compounds VIII–XII are given in Table 2.
The compounds XIII–XVII are colorless crystal-
line substances, readily soluble in most organic solvents.
The developed route of the synthesis is convenient,
simple for processing and provides a wide range of
derivatives of 1-aryl-2-[ω-(dialkylamino)alkyl]-1,2-di-
hydrochromeno[2,3-c]pyrrole-3,9-diones of interest for
searching for the biologically active substances. A
scope of application of this approach to the synthesis
of fused chromone derivatives will be considered in
the future.
2-[2-(Dimethylamino)ethyl]-1-phenyl-1,2-dihydro-
chromeno[2,3-c]pyrrole-3,9-dione (XIIIa). a. A solu-
tion of 0.005 mol of 3-hydroxy-4-(2-hydroxy-ben-
zoyl)-1-[2-(dimethylamino)ethyl]-5-phenyl-1,5-
dihydro-2H-pyrrol-2-one (VIIIa) in 10 ml of glacial
acetic acid was refluxed for 1 h, then cooled, poured
into 100 ml of a mixture of ice and water and
alkalinized with 10% solution of sodium hydroxide to
a pH 8.5–9. The precipitate was filtered off, washed on
the filter with ice water until neutral washings, dried,
and the compound XIIIa was purified by
crystallization.
EXPERIMENTAL
The IR spectra of the substances were recorded on a
Spectrum One (Perkin Elmer) spectrometer with
resolution 1 cm–1 (12 scans) from the tablets with KBr.
The 1H NMR spectra were obtained on a Varian VXR-
300 spectrometer from the solutions in DMSO-d6,
internal reference HMDS.
Similarly were prepared compounds XIIIb–XIIe,
XIVa, XIVe, XVa, XVb, XVe, XVIa–XVIe, XVIIa,
XVIId, XVIIe. Melting points, yields and data of
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 2 2010

328
VYDZHAK, PANCHISHYN
Table 2. Yields, melting points, and elemental analysis data for compounds VIII–XVII
Found, %
Calculated, %
Comp.
no.
mp, °С
(solvent for crystallization)
Yield, %
Formula
C
H
N(Cl)
7.54
C
H
N(Cl)
7.65
85
87
86
76
82
69
74
89
92
76
88
94
90
87
79
92
86
75
71
78
82
61
63
77
68
78
82
71
63
75
71
57
61
68
49
213–215 (ethyl acetate)
219–221 (ethyl acetate)
224–225 (dioxane)
68.71
6.11
C21H22N2O4
C21H21ClN2O4
C21H21N3O6
C22H24N2O5
C23H26N2O6
C23H26N2O4
C24H28N2O5
C23H24N2O5
C23H23ClN2O5
C25H28N2O7
C22H24N2O4
C22H23ClN2O4
C22H23N3O6
C23H26N2O5
C24H28N2O6
C24H26N2O5
C25H28N2O6
C26H30N2O7
C21H20N2O3
C21H19ClN2O3
C21H19N3O5
C22H22N2O4
C23H24N2O5
C23H24N2O3
C24H26N2O4
C23H22N2O4
C23H21ClN2O4
C25H26N2O6
C22H22N2O3
C22H21ClN2O3
C22H21N3O5
C23H24N2O4
C24H26N2O5
C24H24N2O4
C25H26N2O5
68.84
6.05
VIIIa
VIIIb
VIIIc
VIIId
VIIIe
IXа
62.70
61.45
66.70
64.69
69.87
68.05
67.45
62.42
63.91
69.25
63.85
62.36
67.54
65.23
68.41
66.24
64.57
72.46
66.03
64.07
69.98
67.96
73.07
71.23
71.04
64.72
66.97
72.78
66.43
65.03
70.24
67.95
71.03
69.35
5.37
5.08
6.17
6.23
6.52
6.73
6.03
5.19
5.95
6.31
5.70
5.40
6.32
6.56
6.07
6.35
6.42
5.84
5.19
4.77
5.73
5.87
6.11
6.30
5.62
4.83
5.96
6.36
5.60
5.27
5.94
6.44
6.23
6.24
(8.72)
9.96
6.97
6.45
7.14
6.44
6.71
(8.15)
5.80
7.52
(8.39)
10.03
6.58
6.64
6.89
6.33
6.00
8.31
(9.13)
10.84
7.29
6.58
7.48
7.17
6.95
(8.56)
6.50
7.41
(8.57)
10.09
7.39
6.80
6.68
6.19
62.92
61.31
66.65
64.78
70.03
67.91
67.63
62.37
64.09
69.46
63.69
62.11
67.30
65.44
68.23
66.36
64.72
72.40
65.88
64.12
69.83
67.63
73.38
70.92
70.75
65.02
66.66
72.91
66.58
64.86
70.39
68.23
71.27
69.11
5.28
5.14
6.10
6.15
6.64
6.65
5.92
5.23
6.02
6.36
5.59
5.45
6.38
6.41
6.20
6.24
6.27
5.79
5.00
4.87
5.86
5.92
6.43
6.45
5.68
4.98
5.82
6.12
5.33
5.20
6.16
6.20
5.98
6.03
(8.84)
10.21
7.07
6.57
7.10
6.60
6.86
(8.00)
5.98
7.36
(8.55)
9.88
6.82
6.36
6.63
6.19
5.81
8.04
(9.26)
10.68
7.40
6.86
7.44
6.89
7.17
(8.34)
6.22
7.73
(8.93)
10.31
7.14
6.63
6.93
6.45
247–248 (ethyl acetate)
224–226 (ethyl acetate)
214–216 (ethyl acetate)
195–197 (ethyl acetate)
232–234 (ethyl acetate)
229–233 (dioxane)
IXd
Xа
Xb
212–214 (acetonitrile)
194–198 (ethyl acetate)
198–201 (dioxane)
Xe
XIа
XIb
213–215 (dioxane)
XIc
241–242 (ethanol)
XId
242–243 (ethyl acetate)
175–184 (dioxane)
XIe
XIIа
XIId
XIIe
XIIIа
XIIIb
XIIIc
XIIId
XIIIe
XIVа
XIVd
XVа
XVb
XVe
XVIа
XVIb
XVIc
XVId
XVIe
XVIIа
XVIId
184–187 (ethyl acetate)
245–246 (ethyl acetate)
203–204 (ethanol–water, 1:1)
201–202 (ethanol)
229–230 (DMF–ethanol, 1:3)
171–172 (2-propanol)
184–185 (ethanol)
175–176 (ethanol–water, 1:1)
131–132 (2-propanol)
194–195 (DMF–ethanol, 1:4)
179–180 (DMF–ethanol, 1:4)
193–194 (ethanol)
186–187 (ethanol–water, 3:1)
192–194 (ethanol)
168–169 (acetonitrile)
172–173 (ethanol–water, 3:1)
174–175 (ethanol)
200–201 (acetonitrile)
211–212 (DMF–ethanol, 1:5)
57
172–173 (ethanol)
66.98
6.10
6.32
C26H28N2O6
67.23
6.08
6.03
XVIIe
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 2 2010

SYNTHESIS OF 1-ARYL-2-[2-(DIMETHYLAMINO)ETHYL]-1,2-...
REFERENCES
329
elemental analysis of compounds XIII–XVII are
shown in Table 2.
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b. To a solution of 0.005 mol of benzaldehyde in
10 ml of anhydrous methanol was added 0.005 mol of
2-(dimethylamino)ethylamine, the mixture was heated
to 50°C and left standing for 20 min. To the mixture
heated to 30–35°C was added 0.005 mol of methyl o-
hydroxytbenzoylpyruvate, the reaction mixture was
heated to boiling, kept for 30 minutes at a temperature
of 35–40°C, cooled, and to the formed suspension was
added 10 ml of glacial acetic acid, the mixture was
refluxed for 1 h, cooled, poured into 100 ml of a
mixture of ice and water and alkalinized with 10%
solution of sodium hydroxide to pH 8.5–9. The oil was
separated by decanting, washed with ice-cold water,
the residue was ground with water–2-propanol, the
precipitate was filtered off, washed with water–2-
propanol, and compound XIIIa was purified by
crystallization from ethanol. Yield 62%.
Similarly were prepared compound XVe with the
yield 54% and compound XVIIa with the yield 50%.
10. Gein, V.L., Kon’shina, L.O., and Andreichikov, Yu.S.,
Zh. Org. Khim., 1992, vol. 28, no. 10, p. 2134.
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The mixed samples of each compound XIIIa, XVe,
and XVIIa obtained by methods a and b, did not show
1
the melting point depression. Their IR and H NMR
spectra are identical.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 2 2010