Reaction of Nitromethane with Cinnamoyl Derivatives of Cyclic β-dicarbonyl Compounds. Application to the Synthesis of 2(3)-(4-aryl-pyrrolidin-2-ylidene)-1,3(2,4)-diones

Article abstract of DOI:10.1007/s10593-014-1606-0

We have shown that reaction of nitromethane with cinnamoyl derivatives of five- and six-membered carbo- and heterocylic β-dicarbonyl compounds in the presence of 1,1,3,3-tetramethylguanidine proceeds according to the mechanism of 1,4-conjugate addition to the enone fragment of cinnamoyl moiety to give 2(3)-(3-aryl-4-nitrobutanoyl)-substituted cyclic 1,3- or 2,4-diones in good to excellent yields. Chemoselective reduction of nitro function of the latter leads to synthetically useful and biologically interesting 2(3)-(4-arylpyrrolidin-2-ylidene) derivatives.

Full text of DOI:10.1007/s10593-014-1606-0

DOI 10.1007/s10593-014-1606-0
Chemistry of Heterocyclic Compounds, Vol. 50, No. 10, January, 2015 (Russian Original Vol. 50, No. 10, October, 2014)
REACTION OF NITROMETHANE WITH CINNAMOYL
DERIVATIVES OF CYCLIC β-DICARBONYL COMPOUNDS.
APPLICATION TO THE SYNTHESIS OF 2(3)-(4-ARYL-
PYRROLIDIN-2-YLIDENE)-1,3(2,4)-DIONES*
1
1
1
1**
F. S. Pashkovsky , J. S. Dontsu , D. B. Rubinov , and F. A. Lakhvich
We have shown that reaction of nitromethane with cinnamoyl derivatives of five- and six-membered
carbo- and heterocylic β-dicarbonyl compounds in the presence of 1,1,3,3-tetramethylguanidine
proceeds according to the mechanism of 1,4-conjugate addition to the enone fragment of cinnamoyl
moiety to give 2(3)-( 3-aryl-4-nitrobutanoyl)-substituted cyclic 1,3- or 2,4-diones in good to excellent
yields. Chemoselective reduction of nitro function of the latter leads to synthetically useful and
biologically interesting 2(3)-(4-arylpyrrolidin-2-ylidene) derivatives.
Keywords: 2(3)-(4-arylpyrrolidin-2-ylidene)-1,3(2,4)-diones, cyclic β-tricarbonyl compounds, enones,
nitromethane, chemoselectivity, Michael addition, reduction.
The cyclic β-tricarbonyl functionality is an essential structural unit of a great diversity of natural
products. Components of extracts from different plants (leptospermone, humulones, hulupones, filicines, etc.),
various fungal metabolites and antibiotics (chelocardin, dutomicin, usnic acid), pheromones, and the
kairomones of some Lepidoptera species, as well as many others, are cyclic β-triketones [1-3]. Many of these
bioactive compounds exhibit a broad spectrum of useful therapeutic properties and are applied in traditional as
well as in modern medicine. Synthetic benzoyl triketones based on the leptospermone structure template are
currently used as effective agrochemicals (mesotrione, sulcotrione, tembotrione) and therapeutic agents for the
treatment of hereditary tyrosinaemia type I disease (nitisinone, also known as NTBC) [4, 5]. Moreover, carbo-,
as well as heterocyclic β-tricarbonyl compounds, are valuable multifunctional precursors for the synthesis of
natural products and biologically active heterocycles [2, 6-8].
Among cyclic β-tricarbonyls, the compounds in which the keto function of the cinnamoyl substituent is
involved in the β-tricarbonyl fragment are of special interest. Naturally occurring cinnamoyl derivatives of five-
(linderone, lucidone [9], coruscanone B [10]) and six-membered cyclic β-dicarbonyl compounds (champanones
[11], schefflerichalcone [12], saffloquinosides [13], and others) along with their synthetic congeners [14-17],
_______
*Dedicated to Academician G. Duburs on the occasion of his 80th birthday.
**To whom correspondence should be addressed, e-mail: pashkovsky61@mail.ru.
1Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, 5/2 Akademika V. F. Kuprevicha
St., Minsk 220141, Republic of Belarus.
_________________________________________________________________________________________
Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1545-1556, October, 2014. Original
article submitted May 7, 2014.
0009-3122/15/5010-1421©2015 Springer Science+Business Media New York
1421

possess high antibiotic, antifungal, anthelmintic, antimalarial, antiplasmodial, antiparasitic, antidiabetic,
anticancer, anticoagulant, and HIV-1 integrase inhibition activities. Due to the presence of polyunsaturated
system in the structure of cinnamoyl derivatives of cyclic β-dicarbonyl compounds and their acidic character
(vinylogous acids) they are considered to be perspective polarity-sensitive fluorescent probes and acidichromic
colorants [5, 18, 19]. From a synthetic point of view, α,β-unsaturated functionality in the side chain of these
compounds provides additional possibilities for selective chemical reactions at their enone fragment. Thus,
methods for selective reduction of the enone moiety in cinnamoyl substituent of cyclic β-dicarbonyl compounds
developed by us [20, 21] were applied in the synthesis of interphenylene prostanoids and their precursors [22, 23].
The reactivity of different binucleophiles towards the enone system of cinnamoyl derivatives of 6-methyl-
3H-pyran-2,4-dione, 4-hydroxycoumarin, and 4-hydroxy-2-quinolone has been extensively used to synthesize
numerous heterocycles (2-pyrazolines [6, 24, 25], pyridines [26], pyrimidines [27], 1,4-diazepines [28], 1,5-benzo-
diazepines [29], 1,5-benzothiazepines and 1,4-benzothiazines [30]).
Among mononucleophiles, nitroalkanes are of special value. Their conjugate addition to Michael
acceptors is widely used for carbon–carbon bond formation [31]. The ability of the nitro derivatives thus formed
to transform into organic compounds of different classes, including heterocycles [32, 33], promoted their
application as key precursors for the synthesis of dyes, medicines, and agrochemicals. In spite of the fact that
conjugate addition of nitroalkanes to chalcones, substituted cinnamic aldehydes, and cinnamic acid esters has
been extensively studied, a literature survey revealed that nothing was known about reactions of nitroalkanes
with cinnamoyl derivatives of cyclic β-dicarbonyl compounds.
In the present paper, we describe our experimental results that demonstrate 1,4-conjugate Michael
addition of nitromethane to the enone moiety of cinnamoyl derivatives of five- and six-membered carbo- and
heterocyclic β-dicarbonyl compounds for the first time. We also demonstrate the application of the Michael
adducts thus formed in the preparation of new synthetically and biologically useful heterocycles – 2(3)-(4-aryl-
pyrrolidin-2-ylidene)-1,3(2,4)-diones.
Cinnamoyl derivatives of carbo- and heterocyclic β-dicarbonyl compounds 6-10 were obtained by
Claisen–Schmidt condensation of the readily available 2-acetylcyclopentane-1,3-dione (1), 3-acetyltetronic acid
(2), 2-acetyldimedone (3), dehydroacetic acid (4), and 3-acetyl-1-(4-methoxyphenyl)-6-methylpyridine-
2,4(1H,3H)-dione (5) with aromatic aldehydes [22, 34, 35] (Table 1).
The reaction of five- (compounds 6, 7) and six-membered (compounds 8-10) cyclic β-tricarbonyl
compounds with nitromethane was investigated at room temperature. In the reaction, nitromethane served both
as reagent and solvent. Since the compounds 6-10 are vinylogous acids, more than one equivalent of basic
catalyst is necessary. 1,1,3,3-Tetramethylguanidine (TMG) (1.5 equiv.) was applied as the base because its
vinylogous salts were readily soluble in nitromethane, and thus the reaction took place as a homogenous
process.
Ar
Ar
O
O
O
O
X
X
H
H
Z
Z
O
O
A
C
H
H
O
O
O
O
Ar
Ar
X
X
Z
Z
O
D
O
B
1422

It is important to note that, unlike chalcones and cinnamic acid esters, cyclic β-tricarbonyl compounds
exist as equilibrium mixture of endo- (A, B) and exo-cylic (C, D) enol forms, the structure of the main tautomer
being dependent to a great extent on the character of the β-tricarbonyl functionality, the physical state of these
compounds, nature of the solvent used, etc. [5, 36]. Conversion of endo-cyclic tautomers A, B into the
exo-cyclic ones C, D transforms the enone system of the side chain into the diene moiety which makes the
Michael reaction at this fragment problematic. As in the case of the precursors 1-5, cyclic β-tricarbonyl system
of the compounds 6-10 exists in solution in the enol form (B or D), which is confirmed by their NMR spectra
and literature data [17, 22, 28, 34].
TABLE 1. Synthesis of β-Diketone Cinnamoyl derivatives 6-10
Starting tricarbonyl
compound
Yield,
%
R
Method*
A
Reaction product
Mp, °C
Me
143-144
73
1
6
(acetone)
O
O
171-172
(EtOAc)
(171-172
(EtOAc) [22])
CO2Me
A
A
75
73
2
3
7
8
Me
O
O
92-93
H
(EtOAc–pet-
roleum ether,
1:1) (92-93
(EtOAc–pet-
roleum ether,
1:1) [34])
F
B
A
138-139
(2-PrOH)
(140-145
(2-PrOH) [28])
185-189
(EtOAc–pet-
roleum ether,
1:1)
58
83
4
5
9
O
N
O
O
Me
10
Me
Me
OMe
_______
*Method A: compounds 1-3, 5 (1.0 equiv.), aldehyde (0.9 equiv.), piperidine
(1.5 equiv.) in PhH (2 ml/mmol), reflux [22, 34]. Method B: compound 4
(1.0 equiv.), aldehyde (1.0 equiv.) in Py (0.8 ml/mmol), 5 drops of piperidine and
glacial AcOH, 45 min at 45-50°C, then 15 min at 100°C [35].
1423

TABLE 2. 1,4-Conjugate Addition of Nitromethane to the Enone Moiety of
β-Diketone Cinnamoyl Derivatives 6-10
Time, Yield,
Time, Yield,
Michael adduct
Michael adduct
h
%
h
%
72
52
24
62
11
14
15
24
24
47*
89
24
92
12
13
NO2
O
O
O
Me
Me
_______
*Yield of the crude product.
However, under the described conditions nitromethane reacted with compounds 6-10 according to the
scheme of 1,4-conjugate addition to the enone fragment of cinnamoyl moiety to give nitromethyl derivatives
11-15 in 47-92% yield (Table 2). In most cases, the reaction time did not exceed 24 h. The structure of the
obtained compounds was unambiguously assigned on the basis of the spectral data. Compounds 11, 13-15 are
stable, while tetronic acid derivative 12 decomposes during chromatographic purification.
Thus, the described method is a simple general tool for construction of 2(3)-(3-aryl-4-nitrobutanoyl)-
substituted carbo- and heterocylic β-dicarbonyl compounds, which can serve as multifunctional precursors for
new synthetically useful and bioactive derivatives.
As an example, we applied the Michael adducts 11-15 for the preparation of 4-arylpyrrolidin-2-ylidene
derivatives 16-20 of cyclic β-dicarbonyl compounds (Table 3). Synthesis of the latter can be achieved by
chemoselective transformation of the nitro group into the amino function, which is prone to intramolecular
reaction with the carbonyl group of the acyl chain in the intermediates E. Earlier, a similar approach was
employed for the formation of pyrrolidinone moiety in synthetic schemes to obtain antidepressant (S)-rolipram
[37] and alkaloid (+)-9a-epi-stemoamide [38].
For the selective reduction of nitro group in the derivatives 11-15, the use of Raney nickel in the
mixture of methanol and 90% formic acid [39] proved to be the most effective. This system is found to be
compatible with many functionalities including ketones [39]. Reduction of compounds 11, 13-15 by this system
at room temperature leads to 4-arylpyrrolidin-2-ylidene derivatives 16, 18-20 in 47-93% yield (Table 3). The low
yield of enamino dicarbonyl compound 17 under these conditions can be attributed to fast decomposition of
unstable nitromethyl derivative 12 in acidic medium.
The 1H NMR spectra of carbocyclic enamino dicarbonyl compounds 16 and 18 display a broad singlet at 10.46
and 11.88 ppm, respectively, due to the hydrogen-bonded proton of NH group. Examination of the NMR spectra of the
heterocyclic analogs 17, 19, 20 indicates that they are similar to those of the structurally related naturally occurring
allelochemical agent fischerellin A (21) [40] and the alkaloid of marine origin plakoridine C (22) [41].
1424

TABLE 3. Synthesis of 2(3)-(4-Arylpyrrolidin-2-ylidene)-1,3(2,4)-diones 16-20
H2N
O
O
NiRa, 90% HCO2H MeOH
room temp.
11 15
16 20
O
R
E
Yield,
%
2(3)-(4-Arylpyrrolidin-2-ylidene)-1,3(2,4)-dione
(E/Z)-ratio
—
47
1.2:1*2
15
—
93
52
4:1*
4.3:1*
65
_______
*In solution of CDCl3.
*2In solution of DMSO-d6.
1
Thus, as in the case of the aforementioned compounds, the H and 13C NMR spectra of the
enaminodiones 17, 19, 20 are characterized by doubling of most of the signals. The proton of NH group resonates
as two broad signals at 9.89-13.20 ppm. This is due to the fact that this proton can easily form hydrogen bonds
with either the ketone or the ester/amide carbonyl oxygen atom. Hence, like natural compounds 21 and 22, the
enamino dicarbonyl compounds 17, 19, 20 in solution exist as inseparable equilibrium mixtures of enamino
dicarbonyl (E,Z)-rotamers. Interconversion of the latter is believed to proceed via intermediate F [40].
1425

O
O
Me
Me
O
O
O
HN
N
Me
Me
N
H
O
Me
Me
21
22
1
It is generally accepted that in the H NMR spectra of exocyclic enaminodicarbonyl compounds, the
signal of the enamine proton shows the most pronounced downfield shift when this proton is chelated with the
more electron-withdrawing carbonyl group of the ketone rather than that of ester or amide [42, 43]. Taking into
1
account that in the H NMR spectra of compounds 17, 19, 20 the downfield signals of their NH protons are
always more intensive, we can conclude that the (E)-rotamer of these enaminodiones predominates in solutions
of deuterochloroform and dimethyl sulfoxide-d6.
Enaminodiones 16-20 and related compounds are of great synthetic potential because they combine the
ambident nucleophilicity of enamines with the ambident electrophilicity of enones. For this reason, these
compounds can serve as valuable multipurpose precursors for the synthesis of new bioactive heterocycles,
medicines, and other useful compounds [44, 45]. On the other hand, the enaminocarbonyl moiety has long been
known to be a therapeutically valuable pharmacophore [44, 46]. Pyrrolidin- and piperidin-2-ylidene moieties
represent biologically important entities that are present in numerous natural and synthetic biologically active
compounds possessing a broad spectrum of pharmacological (histaminergic, anticonvulsant, anti-inflammatory,
etc.) activity [47]. In light of these facts enaminodiones 16-20 and their congeners are of interest as new
therapeutically useful molecules.
In conclusion, it has been shown that the reaction of nitromethane with cinnamoyl derivatives of carbo-
and heterocyclic β-dicarbonyl compounds in the presence of more than 1 equiv. of 1,1,3,3-tetramethylguanidine
proceeds according to the scheme of 1,4-conjugate addition to the enone fragment of cinnamoyl moiety to give
the corresponding 2(3)-(3-aryl-4-nitrobutanoyl)-substituted carbo- and heterocyclic β-diones in good to
excellent yields. Chemoselective reduction of the nitro group in the latter gives rise to 2(3)-(4-arylpyrrolidin-
2-ylidene) derivatives of cyclic β-dicarbonyl compounds. Further synthetic application of the synthesized
nitromethane Michael adducts and their congeners, in particular, as a source of nitrile oxides in the preparation
of isoxazole and isoxazoline derivatives is currently under investigation.
EXPERIMENTAL
IR spectra were recorded on a FT IR Bomem Michelson 100 spectrometer with Fourier transform.
1H and 13C NMR spectra were acquired on a Bruker Avance 500 spectrometer (500 and 125 MHz, respectively),
1
with the solvent residual signal used as internal standard (CDCl3: 7.26 ppm for H nuclei, 77.0 ppm for 13C
1
nuclei; DMSO-d6: 2.50 ppm for H nuclei, 39.5 ppm for 13C nuclei). DEPT technique was used for
1426

distinguishing carbon signals on the basis of the number of attached protons in 13C NMR spectra. The mass
spectra were recorded using an HPLC-MS/MS system consisting of an Accella chromatograph and LCQ Fleet
mass-selective detector with positive ion detection (APCI, reactant gas – N2). Elemental analyses were
performed on CHN elemental analyzer EuroVector EA3000. Melting points were determined on a Boetius
melting point apparatus. Progress of the reactions was monitored, and the purity of the isolated compounds was
checked by TLC on Silufol UV-254 or Alufol UV-254 plates (Merck), visualization by fluorescence quenching
under UV light. Kieselgel 60 HF254 (Merck) and Kieselgel 60 (Fluka) were used for chromatographic
separation.
β-Diketone Cinnamoyl Derivatives 6, 10 were prepared according to the reported method A [22, 34].
(Е)-2-[3-(p-Tolyl)acryloyl]cyclopentane-1,3-dione (6). Dark-yellow crystals. IR spectrum (KBr), ν,
сm-1: 1190, 1300, 1390 (shoulder), 1415, 1470, 1545 (shoulder), 1565 (shoulder), 1580, 1610 (max.), 1635,
1700. 1Н NMR spectrum (СDCl3), δ, ppm (J, Hz): 2.41 (3Н, s, СН3); 2.59-2.62 (2Н, m, СН2); 2.73-2.76 (2Н, m,
СН2); 7.24 (2Н, d, 3J = 8.0, H Ar); 7.60 (2Н, d, 3J = 8.0, H Ar); 7.89 (1Н, d, 3J = 16.0, С(О)СН=); 8.01 (1Н, d,
3J = 16.0, =СН); the signal of enolic ОН is not visible. 13С NMR spectrum (СDCl3), δ, ppm: 21.7 (СН3); 31.2
(СН2); 34.5 (СН2); 111.4 (С); 117.8 (=СН); 129.5 (2СН Ar); 129.9 (2СН Ar); 131.7 (С); 142.6 (С); 147.7
(=СН); 181.6 (С); 200.6 (С); 209.2 (С). Mass spectrum, m/z (Irel, %): 243 [M+H]+ (100). Found, %: С 74.43;
H 5.85. C15H14O3. Calculated, %: C 74.36; H 5.82.
(Е)-1-(4-Methoxyphenyl)-6-methyl-3-[3-(p-tolyl)acryloyl]pyridine-2,4(1Н,3Н)-dione (10). Yellow
solid. IR spectrum (KBr), ν, сm-1: 1248, 1398, 1468, 1512 (max.), 1531, 1612 (shoulder), 1626 (max.), 1659
(max.). 1Н NMR spectrum (СDCl3), δ, ppm (J, Hz): 1.98 (3Н, s, СН3); 2.34 (3Н, s, СН3); 3.86 (3Н, s, ОСН3);
5.96 (1Н, s, СН=); 7.04 (2Н, d, 3J = 9.0, H Ar); 7.10 (2Н, d, 3J = 9.0, H Ar); 7.12 (2Н, d, 3J = 9.0, H Ar); 7.54 (2Н,
3
3
d, 3J = 9.0, H Ar); 7.88 (1Н, d, J = 16.0, С(О)СН=); 8.53 (1Н, d, J = 16.0, =СН); 16.92 (1Н, s, ОН enolic).
13С NMR spectrum (СDCl3), δ, ppm: 21.5 (СН3); 22.4 (СН3); 55.5 (ОСН3); 101.6 (СН); 105.5 (С); 115.2 (2СН
Ar); 124.4 (СН); 129.1 (2СН Ar); 129.2 (2СН Ar); 129.4 (2СН Ar); 130.7 (С); 132.6 (С); 141.0 (С); 144.8
(СН); 154.2 (С); 159.8 (С); 163.9 (С); 177.9 (С); 194.1 (С). Mass spectrum, m/z (Irel, %): 376 [M+H]+ (100).
Found, %: С 73.56; H 5.61; N 3.75. C23H21NO4. Calculated, %: C 73.58; H 5.64; N 3.73.
1,4-Conjugate Addition of Nitromethane to β-Diketone Cinnamoyl Derivatives 6-10 (General
Method). 1,1,3,3-Tetramethylguanidine (0.19 ml, 1.5 mmol) was added dropwise to a solution or suspension of
cinnamoyl derivative 6-10 (1.0 mmol) in dry MeNO2 (10 ml) upon stirring. The homogeneous reaction mixture was
stirred at room temperature for 24-72 h. After completion of the reaction, MeNO2 was evaporated in vacuo. The
residue was acidified with 1 N HCl (15 ml) at 5°C. Oily products 11, 12 were extracted from the aqueous phase with
CHCl3 (3×15 ml). Organic phases were combined and dried over anhydrous Na2SO4. After evaporation of the
solvent in vacuo, the residue was purified by column chromatography on silica gel (CHCl3–petroleum ether, 9:1).
Solid compounds 13-15 were washed successively with cold 1 N HCl (15 ml) and distilled water (20 ml), then
dried in air and recrystallized from EtOAc.
2-[4-Nitro-3-(p-tolyl)butanoyl]cyclopentane-1,3-dione (11). Light-yellow oil. IR spectrum (thin layer), ν,
1
сm-1: 1379, 1435 (shoulder), 1441, 1553 (max.), 1582 (br.), 1620, 1632, 1639, 1693, 1703. Н NMR spectrum
(СDCl3), δ, ppm (J, Hz): 2.30 (3Н, s, СН3); 2.45-2.53 (2Н, m) and 2.69-2.77 (2Н, m, (СН2)2); 3.23 (1Н, dd,
3
2
3
3
2J = 17.5, J = 6.5) and 3.55 (1Н, dd, J = 17.5, J = 8.0, С(О)СН2); 4.11 (1Н, quint, J = 7.5, СН); 4.60 (1Н,
dd, 2J = 12.5, J = 8.5) and 4.67 (1Н, dd, J = 12.5, J = 7.5, СН2NO2); 7.09-7.17 (4Н, m, H Ar); the signal of
enolic ОН is not visible. С NMR spectrum (СDCl3), δ, ppm: 21.1 (СН3); 27.8 (СН2); 33.4 (СН2); 38.5 (СН);
3
2
3
13
42.0 (СН2); 79.8 (СН2); 114.7 (С); 127.4 (2СН Ar); 129.7 (2СН Ar); 135.4 (С); 137.6 (С); 198.7 (С); 199.7
(С); 203.1 (C). Mass spectrum, m/z (Irel, %): 304 [M+H]+ (100). Found, %: C 63.30; H 5.59; N 4.65. C16H17NO5.
Calculated, %: C 63.36; H 5.65; N 4.62.
Methyl 4-[4-(2,4-Dioxotetrahydrofuran-3-yl)-1-nitro-4-oxobutan-2-yl]benzoate (12). The crude
material is a yellow oil. IR spectrum (thin layer), ν, сm-1: 1379, 1435-1485 (br.), 1556, 1568, 1607-1682 (br.),
1715. 1Н NMR spectrum (СDCl3), δ, ppm (J, Hz): 3.13 (1Н, dd, 2J = 15.5, 3J = 9.0) and 3.29 (1Н, dd, 2J = 15.5,
3J = 5.5, С(О)СН2); 3.87 (3Н, s, СО2СН3); 4.06-4.12 (1Н, m, СН); 4.20 (2Н, br. s, C(O)СН2O); 4.62 (1Н, dd,
1427

3
2
3
3
2J = 13.0, J = 10.0) and 4.79 (1Н, dd, J = 13.0, J = 5.5, СН2NO2); 7.34 (2Н, d, J = 8.5, H Ar); 7.90 (2Н, d,
3J = 8.5, H Ar); the signal of enolic ОН is not visible. 13С NMR spectrum (СDCl3), δ, ppm: 39.9 (СН); 42.6 (СН2);
52.1 (СО2СН3); 70.5 (СН2); 79.4 (СН2); 97.0 (С); 127.8 (2СН Ar); 129.1 (С); 129.9 (2СН Ar); 145.8 (С); 166.9 (С);
177.1 (С); 192.1 (С); 195.4 (С). Mass spectrum, m/z (Irel, %): 350 [M+H]+ (100).
5,5-Dimethyl-2-(4-nitro-3-phenylbutanoyl)cyclohexane-1,3-dione (13). White solid, mp 80-81°С. IR
spectrum (KBr), ν, сm-1: 1381, 1431, 1555 (max.), 1562 (shoulder), 1601, 1664. 1Н NMR spectrum (СDCl3), δ,
ppm (J, Hz): 1.04 (3Н, s, СН3); 1.07 (3Н, s, СН3); 2.34 (2Н, s, СН2); 2.52 (2Н, s, СН2); 3.41 (1Н, dd, 2J = 17.0,
2
3
3
3J = 6.5) and 3.65 (1Н, dd, J = 17.0, J = 7.5, С(О)СН2); 4.14 (1Н, quint, J = 7.5, СН); 4.63 (1Н, dd,
2J = 12.5, 3J = 8.5) and 4.70 (1Н, dd, 2J = 12.5, 3J = 6.5, СН2NO2); 7.26-7.33 (5Н, m, H Ph); 17.59 (1Н, s, ОН
enolic). 13С NMR spectrum (СDCl3), δ, ppm: 28.1 (СН3); 28.2 (СН3); 30.7 (С); 39.5 (СН); 43.8 (СН2); 46.2
(СН2); 52.4 (СН2); 79.8 (СН2); 112.3 (С); 127.6 (2СН Ar); 127.8 (СН Ar); 128.9 (2СН Ar); 139.0 (С); 195.3
(С); 196.8 (С); 202.0 (С). Mass spectrum, m/z (Irel, %): 332 [M+H]+ (100). Found, %: C 65.23; H 6.40; N 4.27.
C18H21NO5. Calculated, %: C 65.24; H 6.39; N 4.23.
3-[3-(4-Fluorophenyl)-4-nitrobutanoyl]-6-methyl-2Н-pyran-2,4(3H)-dione (14). White solid, mp
125-126°С. IR spectrum (KBr), ν, сm-1: 1225, 1387, 1441, 1512, 1556 (shoulder), 1562 (max.), 1603, 1639,
1724. 1Н NMR spectrum (СDCl3), δ, ppm (J, Hz): 2.28 (3Н, s, СН3); 3.42 (1Н, dd, 2J = 18.0, 3J = 6.5) and 3.65
2
3
3
2
3
(1Н, dd, J = 18.0, J = 7.5, С(О)СН2); 4.18 (1H, quint, J = 7.5, СН); 4.61 (1Н, dd, J = 12.5, J = 8.5) and
4.72 (1Н, dd, J = 12.5, J = 6.0, СН2NO2); 5.95 (1Н, s, СН=); 7.02 (2Н, dd, J = 3JНF = 8.5, H Ar); 7.27 (2Н,
2
3
3
dd, 3J = 8.5, JНF = 5.5, H Ar); 15.98 (1Н, s, ОН enolic). 13С NMR spectrum (СDCl3), δ, ppm (J, Hz): 20.8
4
2
(СН3); 38.3 (СН); 44.7 (СН2); 79.7 (СН2); 99.7 (С); 101.4 (СН heterocycl.); 115.9 (d, JCF = 21.3, С-3',5' Ar);
3
1
129.3 (d, JCF = 7.5, С-2',6' Ar); 134.7 (С); 161.1 (С); 162.2 (d, JCF = 245, С–F); 169.7 (С); 180.9 (С); 203.4
(С). Mass spectrum, m/z (Irel, %): 336 [M+H]+ (100). Found, %: C 57.28; H 4.20; N 4.15. C16H14FNO6.
Calculated, %: C 57.32; H 4.21; N 4.18.
1-(4-Methoxyphenyl)-6-methyl-3-[4-nitro-3-(p-tolyl)butanoyl]pyridine-2,4(1Н,3Н)-dione
(15).
White solid, mp 63-66°С. IR spectrum (KBr), ν, сm-1: 1250, 1379, 1410, 1458, 1512, 1551, 1614 (max.), 1659.
1Н NMR spectrum (СDCl3), δ, ppm (J, Hz): 1.99 (3Н, s, СН3); 2.28 (3Н, s, СН3); 3.54 (1Н, dd, 2J = 18.5, 3J = 7.0)
and 3.68 (1Н, dd, 2J = 18.5, 3J = 6.5, С(О)СН2); 3.85 (3Н, s, ОСН3); 4.13-4.19 (1Н, m, СН); 4.54 (1Н, dd, 2J = 12.5,
3J = 9.0) and 4.69 (1Н, dd, 2J = 12.5, 3J = 6.5, СН2NO2); 5.92 (1Н, s, СН=); 7.01-7.09 (6Н, m, H Ar); 7.14 (2Н, d,
3J = 8.0, H Ar); the signal of enolic ОН is not visible. 13С NMR spectrum (СDCl3), δ, ppm: 21.0 (СН3); 22.4 (СН3);
38.6 (СН); 45.7 (СН2); 55.6 (ОСН3); 80.1 (СН2); 101.0 (СН=); 105.5 (С); 115.2 (2СН Ar); 127.5 (2СН Ar); 128.9
(СН Ar); 129.0 (СН Ar); 129.4 (2СН Ar); 130.3 (С); 136.5 (С); 137.1 (С); 154.7 (С); 159.9 (С); 163.6 (С); 176.1
(С); 203.9 (С). Mass spectrum, m/z (Irel, %): 437 [M+H]+ (100). Found, %: C 66.04; H 5.51; N 6.46. C24H24N2O6.
Calculated, %: C 66.04; H 5.54; N 6.42.
Synthesis of enaminodicarbonyl compounds 16-20 from nitromethyl derivatives 11-15 was carried
out according to the literature procedure [39].
2-[4-(p-Tolyl)pyrrolidin-2-ylidene]cyclopentane-1,3-dione (16). White solid, mp 211-212°С. IR
1
spectrum (KBr), ν, сm-1: 1234, 1290, 1481, 1574 (shoulder), 1582, 1620 (max.), 1682. Н NMR spectrum
(СDCl3), δ, ppm (J, Hz): 2.33 (3Н, s, СН3); 2.50-2.52 (2Н, m) and 2.55-2.57 (2Н, m, (СН2)2); 3.32 (1Н, dd,
3
2
3
2J = 19.0, J = 7.0), 3.66-3.73 (2Н, m), 3.79 (1Н, dd, J = 19.0, J = 9.5) and 4.06-4.13 (1Н, m, CH2CHCH2);
7.09 (2Н, d, 3J = 8.0, H Ar); 7.14 (2Н, d, 3J = 8.0, H Ar); 10.46 (1Н, br. s, NH). 13С NMR spectrum (СDCl3), δ,
ppm: 20.9 (СН3); 33.4 (СН2); 34.3 (СН2); 39.6 (СН2); 39.8 (СН); 55.1 (СН2); 105.0 (С); 126.6 (2СН Ar); 129.6
(2СН Ar); 137.1 (С); 138.0 (С); 171.7 (С); 202.2 (С); 205.6 (С). Mass spectrum, m/z (Irel, %): 256 [M+H]+
(100). Found, %: C 75.24; H 6.73; N 5.49. C16H17NO2. Calculated, %: C 75.27; H 6.71; N 5.49.
Methyl (E,Z)-4-[5-(2,4-Dioxodihydrofuran-3(2Н)-ylidene)pyrrolidin-3-yl]benzoate (17). White
solid, mp 251-252°С. IR spectrum (KBr), ν, сm-1: 1244, 1259, 1285, 1493, 1585, 1670 (max.), 1722, 1736
1
2
3
(shoulder). Н NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 3.15 (0.55Н, dd, J = 19.0, J = 8.0, (Е)-isomer),
2
3
3.18 (0.45Н, dd, J = 19.0, J = 7.5, (Z)-isomer), 3.61-3.75 (2Н, m), 3.79-3.83 (1Н, m) and 4.06-4.12 (1Н, m,
CH2CHCH2); 3.84 (3Н, s, СО2СН3); 4.39 (0.9Н, s, C(O)СН2O, (Z)-isomer); 4.43 (1.1Н, s, C(O)СН2O,
1428

3
3
(Е)-isomer); 7.45 (2Н, br. d, J = 8.5, H Ar); 7.93 (2Н, d, J = 8.5, H Ar); 9.89 (0.45Н, br. s, NH, (Z)-isomer);
10.37 (0.55H, br. s, NH, (E)-isomer). 13С NMR spectrum (DMSO-d6), δ, ppm: 38.9 (СН); 39.3 (СН2); 39.6
(СН2); 52.0 (СО2СН3); 54.6 (СН2); 55.3 (СН2); 70.5 (СН2); 71.6 (СН2); 87.1 (С); 88.1 (С); 127.4 (2СН Ar);
128.2 (С); 129.5 (2СН Ar); 147.1 (С); 166.0 (С); 169.6 (С); 169.7 (С); 172.0 (С); 173.3 (С); 193.0 (С); 194.7
(С). Mass spectrum, m/z (Irel, %): 302 [M+H]+ (100). Found, %: C 63.63; H 5.06; N 4.57. C16H15NO5.
Calculated, %: C 63.78; H 5.02; N 4.65.
5,5-Dimethyl-2-(4-phenylpyrrolidin-2-ylidene)cyclohexane-1,3-dione (18). White solid, mp 132-135°С.
1
IR spectrum (KBr), ν, сm-1: 1439, 1556, 1583 (max.), 1643. Н NMR spectrum (СDCl3), δ, ppm (J, Hz): 1.06
(6Н, s, 2СН3); 2.34 (2Н, s, СН2); 2.42 (2Н, s, СН2); 3.45 (1Н, dd, 2J = 19.5, 3J = 6.5), 3.63-3.73 (2Н, m), 3.93 (1Н,
dd, 2J = 19.5, 3J = 9.0) and 4.09 (1Н, dd, 2J = 11.5, 3J = 8.5, CH2CHCH2); 7.21 (2Н, br. d, 3J = 7.0, H-2,6 Ph); 7.26
(1Н, t, 3J = 7.5, Н-4 Ph); 7.33 (2Н, t, 3J = 7.5, Н-3,5 Ph); 11.88 (1Н, br. s, NH). 13С NMR spectrum (СDCl3), δ, ppm:
28.3 (СН3); 28.5 (СН3); 30.5 (С); 40.3 (СН); 43.3 (СН2); 51.8 (СН2); 52.5 (СН2); 54.9 (СН2); 105.6 (С); 126.9
(2СН Ar); 127.2 (СН Ar); 128.9 (2СН Ar); 141.9 (С); 175.2 (С); 196.4 (С); 199.1 (С). Mass spectrum, m/z (Irel, %):
284 [M+H]+ (100). Found, %: C 76.26; H 7.49; N 4.93. C18H21NO2. Calculated, %: C 76.29; H 7.47; N 4.94.
(E,Z)-3-[4-(4-Fluorophenyl)pyrrolidin-2-ylidene]-6-methyl-2Н-pyran-2,4(3H)-dione (19). White
solid, mp 129-133°С. IR spectrum (KBr), ν, сm-1: 1225, 1232, 1275, 1462, 1475, 1514, 1564 (shoulder), 1591
1
(max.), 1659, 1709. Н NMR spectrum (СDCl3), δ, ppm (J, Hz): 2.15 and 2.17 (3Н total, 2s, СН3, (E)- and
2
3
2
3
(Z)-isomers); 3.45 (0.8Н, dd, J = 19.5, J = 6.5, (Е)-isomer), 3.56 (0.2Н, dd, J = 19.0, J = 6.5, (Z)-isomer),
2
3
2
3
3.70-3.80 (2Н, m), 3.93 (1Н, dd, J = 19.5, J = 9.0), 4.08 (0.2Н, dd, J = 20.0, J = 8.5, (Z)-isomer) and 4.19
(0.8Н, dd, 2J = 11.5, 3J = 8.5, (Е)-isomer, CH2CHCH2); 5.72 and 5.74 (1Н total, 2s, СН=, (E)- and (Z)-isomers);
3
3
3
4
7.03 (2Н, dd, J = 8.5, JНF = 8.5, H Ar); 7.19 (2Н, dd, J = 8.5, JНF = 5.5, H Ar); 10.63 (0.2Н, br. s, NH,
(Z)-isomer); 12.39 (0.8Н, br. s, NH, (Е)-isomer). 13С NMR spectrum (СDCl3), δ, ppm: 19.8 (СН3, (Z)-isomer);
20.1 (СН3, (Е)-isomer); 39.3 (СН pyrrolidine, (Е)-isomer); 40.0 (СН pyrrolidine, (Z)-isomer); 43.2 (СН2,
(Z)-isomer); 43.5 (СН2, (Е)-isomer); 55.0 (СН2, (Z)-isomer); 56.0 (СН2, (Е)-isomer); 94.6 (С, (E)- and
2
(Z)-isomers); 107.4 (СН=, (Е)-isomer); 109.4 (СН=, (Z)-isomer); 115.9 (d, JCF = 21.3, СН-3',5' Ar, (E)- and
(Z)-isomers); 128.4 (d, 3JCF = 7.5, СН-2',6' Ar, (E)- and (Z)-isomers); 137.2 (С, (E)- and (Z)-isomers); 162.0 (d,
1JCF = 245, С–F, (E)- and (Z)-isomers); 163.8 (2С, (E)- and (Z)-isomers); 176.9 (С, (Z)-isomer); 177.5 (С,
(Е)-isomer); 181.3 (С, (Z)-isomer); 184.2 (С, (Е)-isomer). Mass spectrum, m/z (Irel, %): 288 [M+H]+ (100).
Found, %: C 66.86; H 4.87; N 4.85. C16H14FNO3. Calculated, %: C 66.89; H 4.91; N 4.88.
(E,Z)-1-(4-Methoxyphenyl)-6-methyl-3-[4-(p-tolyl)pyrrolidin-2-ylidene]pyridine-2,4(1H,3H)-dione
(20). White solid, mp 189-190°С. IR spectrum (KBr), ν, сm-1: 1248, 1294, 1466, 1512, 1574, 1622 (max.),
1649. 1Н NMR spectrum (СDCl3), δ, ppm (J, Hz): 1.85 and 1.87 (3Н total, 2s, СН3, (Е)- and (Z)-isomers); 2.31,
2
3
2.33 (3Н total, 2s, СН3, (Е)- and (Z)-isomers); 3.49 (0.81Н, dd, J = 19.5, J = 7.0, СНαНβ (Е)-isomer);
2
3
3.61-3.71 (1.38Н, m, СН (E)- and (Z)-isomers, СНαНβ (Z)-isomer); 3.75 (0.81Н, dd, J = 12.0, J = 7.0,
2
NHСНαНβ (Е)-isomer); 3.83 and 3.85 (3Н total, 2s, ОСН3, (Е)- and (Z)-isomers); 3.96 (0.81Н, dd, J = 19.5,
3J = 9.5, СНαНβ (Е)-isomer); 4.04 (0.19Н, dd, 2J = 10.5, 3J = 8.5, NHСНαНβ (Z)-isomer); 4.11-5.15 (0.19Н, m,
NHСНαНβ (Z)-isomer); 4.15 (0.81Н, dd, 2J = 12.0, 3J = 9.0, NHСНαНβ (Е)-isomer); 5.77 and 5.79 (1Н total, 2s,
СН= (Е)- and (Z)-isomers); 6.96-7.02 (2Н, m, H Ar); 7.07-7.14 (6Н, m, H Ar); 11.59 (0.19Н, s, NH,
(Z)-isomer); 13.20 (0.81Н, s, NH, (Е)-isomer). 13С NMR spectrum (СDCl3), δ, ppm: (E)-isomer: 21.0 (СН3);
22.0 (СН3); 39.8 (СН); 43.2 (СН2); 55.48 (СН2); 55.51 (ОСН3); 100.6 (С); 107.9 (СН=); 114.8 (2СН Ar);
126.6 (2СН Ar); 129.5 (2СН Ar); 129.8 (2СН Ar); 131.5 (С); 136.7 (С); 138.8 (С); 149.9 (С); 159.3 (С); 165.6
(С); 178.0 (С); 183.1 (С); (Z)-isomer: 21.0 (СН3); 21.6 (СН3); 40.3 (СН); 43.3 (СН2); 54.8 (СН2); 55.5 (ОСН3);
100.6 (С); 110.7 (СН=); 114.8 (2СН Ar); 126.7 (2СН Ar); 129.5 (2СН Ar); 129.7 (2СН Ar); 131.5 (С); 136.8
(С); 138.8 (С); 148.3 (С); 159.5 (С); 168.1 (С); 177.2 (С); 181.2 (С). Mass spectrum, m/z (Irel, %): 389 [M+H]+
(100). Found, %: C 74.18; H 6.21; N 7.24. C24H24N2O3. Calculated, %: C 74.21; H 6.23; N 7.21.
The authors thank the Belorussian Foundation for Basic Research (grant X12P-083) for financial
support.
1429

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