Synthesis and cytotoxic activity of 4-substituted 3-cyano-6,6-dimethyl-5,6- dihydro-2-pyranones

Article abstract of DOI:10.1023/B:COHC.0000040766.10102.81

The respective 4-(arylvinyl)lactones and compounds of the Michael adduct type were synthesized by the condensation of substituted benzaldehydes with 3-cyano-4,6,6-trimethyl-5,6-dihydro-2-pyranone in the presence of catalytic amounts of sodium hydroxide. I

Full text of DOI:10.1023/B:COHC.0000040766.10102.81

Chemistry of Heterocyclic Compounds, Vol. 40, No. 6, 2004
SYNTHESIS AND CYTOTOXIC ACTIVITY
OF 4-SUBSTITUTED 3-CYANO-
6,6-DIMETHYL-5,6-DIHYDRO-2-PYRANONES
L. Leite, D. Jansone, M. Fleisher, H. Kazhoka, J. Popelis, N. Veretennikova,
I. Shestakova, I. Domracheva, and E. Lukevics
The respective 4-(arylvinyl)lactones and compounds of the Michael adduct type were synthesized by the
condensation of substituted benzaldehydes with 3-cyano-4,6,6-trimethyl-5,6-dihydro-2-pyranone in the
presence of catalytic amounts of sodium hydroxide. It was shown by the semiempirical AM1 method that
the indicated products can be formed through one and the same intermediate compound. Some of the
synthesized phenylvinyl-5,6-dihydro-2-pyranones have a cytotoxic effect, and this corresponds to the
prognosis of the OREX expert system.
Keywords: benzaldehyde, substituted δ-lactones, crotonic condensation mechanism, semiempirical
AM1 method, cytotoxic activity, OREX expert system.
We have shown that the reaction of methyl-substituted γ- and δ-lactones with pyridinecarbaldehydes
takes place by a nontraditional mechanism, in which the products from the reaction of one molecule of the
aldehyde with two molecules of the pyranone are formed in addition to the products from crotonic condensation
[1]. At the same time no departures from the classical mechanism of crotonic condensation were found in [2, 3],
devoted to the condensation of benzaldehyde with the above-mentioned lactones,
The aim of the present work was to investigate the condensation of 3-cyano-4,6,6-trimethyl-5,6-dihydro-
2-pyranone (1) with substituted benzaldehydes 2-10 in greater detail and to determine the effect of the electronic
structure of the aldehyde on the ratio of the two paths of condensation with the CH acid.
Earlier we showed that 3-cyano-6,6-dimethyl-4-[2-(4-nitrophenyl)vinyl]-5,6-dihydro-2-pyranone, like
its analogs with pyridyl-containing substituents, have clearly defined cardiovascular activity [1]. The second aim
of the work was therefore to analyze the potential biological activity of the synthesized compounds using the
OREX system (optimized recognizing expert system), developed at the Latvian Institute of Organic Synthesis,
and also to verify experimentally the established structure–activity relation.
The reaction of the aldehydes 2-10 with the pyranone 1 was carried out in ethanol in the presence of
catalytic amounts of sodium hydroxide with the pyranone, aldehyde, and sodium hydroxide in molar ratios of
(0.7-2):1:(0.06-0.13). The initial concentration was 1.87 M for the pyranone and 0.93 M for the aldehydes.
According to the data in Table 1, two types of compounds (the products of crotonic condensation 11-19 and
compounds of the Michael adduct type 20-28) are formed as a result of the reaction of all the aldehydes with the
pyranone 1, and the times at which they appear and the yields depend on the nature of the substituent of the
aldehyde and on the temperature.
__________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga LV-1006, Latvia; e-mail: leite@osi.lv. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 839-849, June, 2004. Original article submitted
December 17, 2003.
0009-3122/04/4006-0715©2004 Plenum Publishing Corporation
715

To compare the reactivity of the benzaldehydes with various substituents the yields of the reaction
products were determined by HPLC without isolation from the reaction mixture. The dynamics of the process
were monitored by TLC.
As seen from Table 1, in the reaction of the unsubstituted aldehyde 2 with pyranone a product of the
Michael adduct type 20 is formed preferentially irrespective of the reaction temperature and the molar ratio of
the reagents. The yield of this compound increases with increase in the amount of the catalyst and the reaction
time. The appearance of the crotonic condensation product 11 was only observed after 4 h.
1
2
R
R
N
O
O
R
1
2
R
R
N
O
_
11 19
R
+
H
N
O
O
2
R
1
R
_
O
O
1
2 10
CH CH2
_
R
2
20 28
2, 11, 20 R = R1 = R2 = H; 3, 12, 21 R = NO2, R1 = R2 = H; 4, 13, 22 R = Cl, R1=R2 = H;
5, 14, 23 R = Cl, R1 = H, R2 = Cl; 6, 15, 24 R = NMe2, R1 = R2 = H;
7, 16, 25 R = Me, R1 = R2 = H; 8, 17, 26 R = OH, R1 = R2 = H;
9, 18, 27 R = OMe, R1 = R2 = H; 10, 19, 28 R = OH, R1 = OMe, R2 = H
It was not possible to isolate the products from the reaction of the pyranone 1 and the aldehyde 8.
However, to judge from the data from chromatography and from the 1H NMR spectrum two compounds 17 and
26 are formed. With the pyranone and aldehyde 3 in a ratio of 2:1 compound 21 is mainly formed. However, on
account of the effect of the electron-withdrawing substituent NO2 the yield is lower than in the case of the
unsubstituted aldehyde. Only if the molar ratio of the aldehyde and pyranone is 1.5:1 can the product of the
Michael adduct type no longer be detected in the reaction products.
In the case of the electron-donating substituent NMe2 (aldehyde 6), as expected, the reaction rate is
greatly reduced, and more than 76% of the pyranone remains unreacted even after keeping the reaction mixture
for 4 h. The yield of the product 24 in this case is only 1.7%.
The structure of the obtained lactones was proved on the basis of the 1H NMR spectra (Tables 2 and 3).
1
According to the H NMR spectra, the vinyl fragment of compounds 11-16, 18, and 19 has the trans
configuration (3J = 15.9-16.2 Hz).
Comparison of the changes in the chemical shifts of the two vinyl protons with replacement of the
substituent in the phenyl ring provides grounds for assigning the downfield doublet to the absorption of the
proton at the C atom attached to the phenyl group (range of variation of the chemical shifts ∆δ = 0.42 ppm),
while the upfield doublet is assigned to the absorption of the proton at the C atom attached to the pyranone
residue (∆δ = 0.26 ppm).
Attention is drawn to the fact in the spectra of the lactones 11-16, 18, and 19 the protons the of CH2 and
the protons of the two methyl groups in the pyranone ring are magnetically equivalent, whereas in the lactones
20-28 the chemical shifts of the same protons differ (0.04-0.16 and 0.02-0.17 ppm respectively). Dreiding
models show that the pyranone ring has the form of a distorted half-chair and the rate of the conformational
transitions changes with replacement of the substituent at position 2 of the pyranone. Magnetic nonequivalence
is also observed for the CH2 protons of the –CH(CH2)2– fragments of compounds 20-28 (2J = 12.4-13.2 Hz).
This may be due to the considerable size of the substituted pyranones, which prevents free rotation about the
CH2–pyranone bond.
716

TABLE 1. Reaction of the Pyranone 1 with Benzaldehydes 2-10 at 78°C
Aldehyde–
pyranone–NaOH
molar ratio
Yield of reaction products, %
Time, h
Aldehyde
Crotonic
Adduct of Michael reaction type
condensation
2
2
1 : 1 : 0.06
1 : 2 : 0.06
1 : 2 : 0.06
1 : 2 : 0.13
1 : 2 : 0.06
1 : 0.7 : 0.06
1 : 2 : 0.06
1 : 2 : 0.06
1 : 2 : 0.06
1 : 2 : 0.06
1 : 2 : 0.06
1 : 2 : 0.06
1 : 2 : 0.06
2.5*
1
—
—
63.5
41.5
57.6*3
81.4
75.3*5
—
52.7
52.0
1.7*7
22.7
21.7
39.8
13.2
2
4
3.1*2
—
2
4
3
4
22.6*4
60.0
15.2
33.3
11.7*6
10.9
24.6
14.8
37.9
3
4
4
4
5
4
6
4
7
0.1
0.5
1
8
9
10
0.5
_______
* Reaction temperature 20°C.
*2 Formed after 4 h.
*3 Formed 15 min after mixing of the reagents.
*4 Formed at moment the reagents were mixed.
*5 Formed after 5 min.
*6 Formed after 1 h.
*7 Formed after 3 h.
According to our views about the mechanism of the crotonic condensation of pyridinecarbaldehydes
with furanone, the two products from the reaction of benzaldehydes with pyranone 1 can be formed through one
and the same intermediate product of aldol condensation type A, and the probable source of the protons is
hydrated sodium cations [3].
In the present the model condensation of the pyranone 1 with the aldehyde 3 was studied by the
semiempirical quantum-chemical AM1 method [4]. The JMol software [5] was used for visualization and
animation of the obtained results, and the ChemCraft 1.3 software package [6] was used to create a design of the
reaction system. It was assumed that by analogy with the reaction of pyridinecarbaldehydes the reaction of
pyranone and the aldehyde 3 will take place in two directions depending on the nature of the attacking
nucleophile:
+
HOH
H
C
–
–
OH
I
HetC
H
2
(3)
Ar
C
ArCH CHHet
Het
ArCH(CH2Het)2
(1)
(2)
12
21
II
H
H1
N
A
NO2
Me
Me
;
=
Ar =
Het
O
O
717

TABLE 2. The 1H NMR Spectra of the Lactones 11-16, 18, and 19
Found, %
Calculated, %
H
——————
Com-
pound
Empirical
formula
mp, °C
1Н NMR (CDCl3), δ, ppm (J, Hz)
C
N
11
12
13
14
C16H15NO2
75.87
75.87
5.97
5.97
5.54
5.53
144-146
224-226
180-182
212-214
1.52 (6H, s, CH3 pyranone); 2.87 (2H, s, CH2 pyranone); 7.29 and 7.45 (2H, d and d,
J = 16.2, CH=CH); 7.3-7.7 (5H, m, С6Н5)
C16H14N2O4
C16H14ClNO2
C16H13Cl2NO2
64.40
64.42
4.67
4.73
9.35
9.39
1.55 (6H, s, CH3 pyranone); 2.88 (2H, s, CH2 pyranone); 7.31 and 7.54 (2H, d and d,
J = 16.2, CH=CH); 7.76 (2H, m, J = 9.0, С6Н4 H2, H6); 8.3 (2H, m, J = 9.0, С6Н4 H3, H5)
66.74
66.79
4.84
4.90
4.88
4.87
1.53 (6H, s, CH3 pyranone); 2.86 (2H, s, CH2 pyranone); 7.25 and 7.46 (2H, d and d,
J = 16.1, CH=CH); 7.42 (2H, m, J = 8.9, С6Н3 H2, H6); 7.55 (2H, m, J = 8.9, С6Н4 H3, H5)
59.69
59.65
4.06
4.07
4.29
4.35
1.55 (6H, s, CH3 pyranone); 2.88 2H, s, CH2 pyranone); 7.34 1H, dd, J = 8.6 and 2.0, С6Н3 H5)
7.38 and 7.63 (2H, d and d, J = 16.2, CH=CH); 7.47 (1H, d, J = 2.0, С6Н3 H3);
7.74 (1H, d, J = 8.6, С6Н3 H6)
C18H20N2O2
C17H17NO2
72.88
72.95
6.75
6.80
9.40
9.45
192-194
143-145
1.50 (6H, s, CH3 pyranone); 2.81 (2H, s, CH2 pyranone); 3.08 (6H, s, N(CH3)2;
6.68 (2H, m, J = 9.0, С6Н4 H2, H6); 7.22 (2H, s, CH=CH); 7.51 (2H, m, J = 9.0, С6Н4 H3, H5)
15
16
76.36
76.38
6.40
6.41
5.26
5.24
1.52 (6H, s, CH3 pyranone); 2.40 (3H, s, CH3С6Н4); 2.85 (2H, s, CH2 pyranone);
7.24 (2H, m, J = 8.2, С6Н4 H3, H5), 7.26 and 7.39 (2H, d and d, J = 15.6, CH=CH);
7.51 (2H, m, J = 8.2, С6Н4 H2, H6)
C17H17NO3
C17H17NO4
72.06
72.07
6.06
6.05
4.93
4.94
139-141
1.51 (6H, s, CH3 pyranone); 2.84 (2H, s, CH2 pyranone); 3.87 (3H, s, OCH3);
6.95 (2H, m, J = 8.9, С6Н4 H2, H6); 7.25 and 7.31 (2H, d and d, J = 15.9, CH=CH);
7.58 (2H, m, J = 8.9, С6Н4 H3, H5)
18
19
68.19
68.22
5.72
5.72
4.66
4.68
233-236 (dec.) 1.42 (6H, s, CH3 pyranone); 3.09 (2H, s, CH2 pyranone); 3.84 (3H, s, OCH3);
6.89 (1H, d, J = 7.8, С6Н3 H5); 7.12 and 7.64 (2H, d and d, J = 15.9, CH=CH);
7.2-7.4 (2H, m, С6Н3 H2, H6); 10.0 (1H, s, OH)

TABLE 3. The Characteristics of the Lactones
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
1Н NMR (DMSO-d6), δ, ppm (J, Hz)
mp, °C
C
H
N
20
21
C25H26N2O4
C25H25N3O6
71.72
71.75
6.26
6.26
6.70
6.69
188-192
1.23 and 1.25 (12H, s and s, CH3 of pyranone); 2.33 and 2.49 (4H, d and d, J = 18.9, CH2 of pyranone); 3.00 (2H, dd,
J = 12.4 and 10.4 CH(CH2)2; 3.09 (2H, dd, J = 12.4 and 5.6 CH(CH2)2; 3.49 (1H, m, CH); 7.2-7.5 (5H, m, C6H5)
64.65
64.79
5.42
5.44
9.03
9.07
204-207
(dec.)
1.22 and 1.35 (12H, s and s, CH3 of pyranone); 2.75 and 2.80 (4H, d and d, CH2 of pyranone);
3.02 and 3.08 (4H, m and m, CH(CH2)2; 3.71 (1H, m, CH); 7.68 2H, m, J = 9.6, C6H4 H2 and H6);
8.18 (2H, m, J = 9.6, C6H4 H3, H5)
22
23
25
C25H25ClN2O4 66.27
66.30
5.57
5.56
6.14
6.18
183-185
(dec.)
1.18 and 1.32 (12H, s and s, CH3 of pyranone); 2.75 and 2.81 (4H, d and d, CH2 of pyranone);
3.00 and 3.04 (4H, m and m, CH(CH2)2; 3.51 (1H, m, CH); 7.40 (4H, s, C6H4)
C25H24Cl2N2O4 61.63
61.61
4.87
4.96
5.69
5.75
212-214
1.23 and 1.30 (12H, s and s, CH3 of pyranone); 2.73 and 2.77 (4H, d and d, CH2 of pyranone);
3.05 and 3.11 (4H, m and m, CH (CH2)2; 3.97 (1H, m, CH); 7.4-7.8 (3H, m, C6H3)
C26H28N2O4
72.16
72.20
6.52
6.53
6.47
6.48
185-187
1.16 and 1.33 (12H, s and s, CH3 of pyranone); 2.25 (3H, s, CH3C6H4); 2.73 and 2.82 (4H, d and d,
J = 19.1, CH2 of pyranone); 2.95 and 3.04 (4H, m and m, CH(CH2)2; 3.50 1H C6H4 (1H, m, CH);
7.12 (2H, m, J = 7.8, C6H4 H2, H6); 7.22 (2H, m, J = 7.8, C6H4 H3, H5)
26
27
28
C25H26N2O5·
0.5 H2O
67.76
67.71
6.18
6.14
6.26
6.32
157-160
(dec.)
1.16 and 1.31 (12H, s and s, CH3 of pyranone); 2.72 and 2.79 (4H, d and d, CH2 of pyranone);
2.8-3.1 (4H, m, CH(CH2)2; 3.35 (1H, m, CH); 6.68 (2H, m, J = 8.5, C6H4 H2, H6);
7.14 (2H, m, J = 8.5, C6H4 H3, H5); 9.37 (1H, s, OH)
C26H28N2O5
69.54
69.63
6.24
6.29
6.30
6.25
193-196
(dec.)
1.16 and 1.32 (12H, s and s, CH3 of pyranone); 2.72 and 2.83 (2H, d and d, J = 19.2, CH2 of pyranone);
2.95 and 3.03 (4H, m and m, CH(CH2)2; 3.50 (1H, m, CH); 3.71 (3H, s, OCH3);
6.87 (2H, m, J = 8.6, C6H4 H2, H6); 7.26 (2H, m, J = 8.6, C6H4 H3, H5)
C26H28N2O6·
0.5 C2H5OH·
0.5 H2O
65.55
65.31
6.31
6.50
5.63
5.64
158-160
(dec.)
1.23 and 1.33 (12H, s and s, CH3 of pyranone); 2.70 and 2.86 (4H, d and d, J = 19.1, CH2 of pyranone);
3.10 (2H, dd, J = 13.2 and 5.6, CH(CH2)2; 3.23 (2H, dd, J = 13.2 and 10.0, CH(CH2)2; 3.57 (1H, m, CH);
3.90 (3H, s, OCH3); 6.72 (1H, d, J = 8.0, C6H3 H5); 6.78 (1H, dd, J = 8.0 and 1.8, C6H3 H6);
7.10 (1H, d, J = 1.8, C6H3 H2); 7.71 (1H, s, OH)

а
b
c
Fig. 1. Reaction of the intermediate compound A with the OH- ion:
a) the starting position; b) elimination of the H2O molecule; c) the reaction products.
Thus, the reaction of the intermediate A with the OH- ion can lead to the product from crotonic
condensation 12. At the starting position the OH- ion is on an extension of the C(2)–H(1) bond at a distance of 3.10
Å from the H(1) atom (Fig. 1a).
If this distance is reduced to 2.86 Å a molecule of water is eliminated from the C(1) atom. Subsequently,
the H(1) atom is removed from the C(2) atom by the action of the OH- ion, and this leads to the formation of
another molecule of water and the product 12 (Fig. 1c). Thus, this reaction path is realized by an E2 mechanism.
The length of the double bond in compound 12 of 1.35 Å corresponds to data in [7]. The calculations show that
the reaction takes place spontaneously without an energy barrier. The enthalpy of this reaction is -1011.7 kJ/mol.
Figure 2a shows the selected starting position during calculation of the reaction system containing the
-
intermediate compound A and the ion HetC(3)H2 . The C(3)–C(1) and C(3)–H(1) distances are 5.14 and 3.30 Å
-
respectively. The HetC(3)H2 ion, in which the C(3) atom is negatively charged (-0.386), attacks the positively
а
b
-
Fig. 2. Reaction of the intermediate product A and the ion HetCH2 :
a) the initial state; b) the reaction products (compound 21 and a water molecule).
720

charged C(1) atom (0.146) of the intermediate compound A. When the C(3)–C(1) distance decreases to 4.89 Å, a
molecule of water is eliminated from the C(1) atom. Further decrease of the distance between the C(3) and C(1)
atoms to 1.523 Å leads to the formation of compound (21) (Fig. 2b). At this moment the distance between the
water molecule and the C(1) atom amounts to 4.09 Å. During visualization of the process it is possible to see how
gradual Walden inversion of the configuration at the C(1) atom occurs in the course of the reaction. The
-
calculations show that the reaction of the HetC(3)H2 ion with the intermediate A takes place spontaneously
without the need to overcome an energy barrier. The heat of this reaction amounts to -697.1 kJ/mol.
Earlier it was shown by calculation that reaction of deprotonated at methyl group furanone with an
intermediate compound takes place regioselectively during the condensation of 3-cyano-4,5,5-trimethyl-2(5H)-
furanone with 3-pyridinecarbaldehyde [3]. Thus, if attack by the indicated anion was directed at the C(1) atom of
the intermediate compound (having a structure similar to compound A in the present work), bimolecular
nucleophilic substitution (SN2) occurred, resulting in the formation of a product of the Michael adduct type. At
the same time the ethenyl derivative of furanone and the initial furanone are formed as a result of attack at the
H(1) atom, i.e., an E2 bimolecular elimination reaction occurs.
As follows from the results of the quantum-chemical analysis, in the case of the reaction of the pyranone
1 with the aldehyde 3 in the reaction of the intermediate compound A with the deprotonated pyranone only the
product of the Michael adduct type is formed, irrespective of the direction of attack by the anion. This may
explain the fact that the yield of the product 21 under similar conditions is higher that the yield of the compound
of the same type produced by the reaction of 3-cyano-4,5,5-trimethyl-2(5H)-furanone with
3-pyridinecarbaldehyde (81.5 and 59.5% respectively).
Thus, the results of the present work indicate that the reactions of δ- and γ-methyllactones with aryl and
hetaryl aldehydes are fairly general in nature and involve the formation not only of the crotonic condensation
product but also a product of the Michael adduct type.
The OREX expert system [8, 9] was used to predict the biological activity of the synthesized
compounds. OREX is a system of programs for the creation and analysis of a data base and knowledge base and
also for predicting biological activity. The algorithms of the logic-structural approach are based on the selection
and subsequent incorporation of reliable indicators of biological activity, i.e., the structural fragments that
determine the type of biological activity. The description of the chemical structure was based on descriptor
centers and graphs representing the topology of the molecule. The program codes the structure of the compounds
on the basis of the descriptor centers, singling out descriptors that are in the final count an abstract representation
of the structure. The activity indicators are selected from the set of descriptors according to the working rules of
a system of the following type:
P
f
A
if the compound has indicator f, it will then exhibit activity A with probability P.
The indicators are selected according to their statistical value, determined in the data base employed as
statistical sample. During screening of the compounds that we synthesized in the OREX program it was shown
that the phenylvinyl derivative of the γ-lactone may have anticancer activity. It is possible to state with some
degree of probability that the mechanism of their action involves the inhibition of RNA synthesis and also
necrosis of the tumor in the respective systems (Fig. 3).
The cytotoxic activity of the synthesized compounds on a monolayer strain of tumor cells MG-22A
(mouse hepatoma) and their ability to stimulate the biosynthesis of nitric oxide radicals (NO·), one of the
possible components of the cytotoxic effect, were tested on the basis of the prediction results (Table 4). The
strongest cytotoxic effect is exhibited by the nitrophenylvinyl and chlorophenyl derivatives of pyranone
(compounds 12 and 13), which at low concentrations (5 and 6 µg/ml) secure the destruction of cells of the
MG-22A line. The pyranone 13 is characterized by a high level of generation of NO· in the cells (800%,
coloration CV), which may explain its high cardiovascular activity [1].
721

.
Fig. 3. Prediction of the activity in OREX.
Total is the total amount of the compounds containing the given descriptor in the data base;
Active is the number of active compounds containing the given descriptor in the data base;
Conf. is the confidence coefficient, indicating the lowest level of probability with which the compound
possessing the given activity indicator actually exhibits this activity;
Effic. is the coefficient of efficiency, indicating by how many times the compound possessing this
indicator has a higher probability of exhibiting the given activity than any compound taken at random;
Covering is the covering coefficient and shows what part of the active compounds possesses a given
indicator.
722

TABLE 4. The Biological Effect of Phenyllactones (in vitro) on a
Monolayer Culture of MG-22A
Cytotoxicity, µg/ml*
Generation of NO·
(100% CV)
Compound
TD50 (CV)
TD50 (MTT)
11
12
13
14
15
16
18
19
20
22
23
25
26
27
28
26
5
48
33
17
75
67
21
800
17
5
6
58
2
2
*
*
28
34
42
32
50
50
6
2
2
*
*
2
2
*
*
9
52
58
300
15
53
11
9
2
2
*
*
55
74
2
2
*
*
2
2
*
*
2
2
*
*
7
_______
* TD50 is the concentration securing 50% destruction of cells, µg/ml; CV is
coloration with crystal violet; MTT is coloration with 3-(4,5-dimethyl-2-
thiazolyl)-2,5-diphenyltetrazolium bromide [10, 11]; the nitric oxide was
determined by Grace's method in the culture medium a over cells and
converted to 100% live cells with coloration by CV [10].
*2 There was no cytotoxic effect.
EXPERIMENTAL
The yield of the reaction products was determined by HPLC on a Nova-Pak Silica column
(3.9 × 150 mm). The delivery rate of the eluant (1:1 ethyl acetate–hexane) was 1.5 ml/min, UV detector, 254 nm.
1
The H NMR spectra were recorded on a Mercury 200B instrument (200 MHz) in deuterochloroform and
DMSO-d6 with TMS as internal standard. TLC was conducted on Silufol UV-254 plates with 1:1 ethyl acetate–
hexane as eluant.
The quantum-chemical calculations were carried out by the semiempirical AM1 method using MOPAC
6 software with full optimization of the geometry of the reagents, reaction system, and reaction products in the
EF regime at the PRECISE level.
Condensation of 3-Cyano-4,6,6-trimethyl-5,6-dihydro-2-pyranone with Benzaldehyde (General
Procedure). A mixture of pyranone 1, aldehyde 2-10, and sodium hydroxide in ethanol was heated with stirring
to boiling and boiled for 4 h or kept at room temperature. The product of the Michael adduct type that separated
was filtered off without cooling the mixture. After cooling to room temperature the ethenyl derivative of the
lactone was filtered off. Both products were purified by recrystallization from ethanol.
The enthalpy of reaction was calculated as the difference between the total energy of the final state of the
-
system and the sum of the total energies of the isolated reagents – the anion (OH- or HetC(3)H2 ) and the
intermediate.
Additional information on the changes in geometry during the reaction can be obtained on request from
the authors (e-mail: misha@osi.lv).
723

The work was carried out with financial support from the Latvian Council on Science (Program
"Development of Modern Methods of Organic Chemistry with the Aim of Establishing the Industrial Production
of New Medicinal Preparations in Latvia").
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