Synthesis and reactivity of methyl 3-acyl-6-amino-4-aryl-5-cyano-4h-pyran- 2-carboxylates

Article abstract of DOI:10.1007/s10593-012-1091-2

By treating arylidenemalononitriles with methyl 2,4-dioxobutanoates, derivatives of 4H-pyrans - methyl 3-acyl-6-amino-4-aryl-5-cyano-4H-pyran-2- carboxylates - are obtained, which are novel, promising structural components for the synthesis of carbo- and

Full text of DOI:10.1007/s10593-012-1091-2

Chemistry of Heterocyclic Compounds, Vol. 48, No. 7, October, 2012 (Russian Original Vol. 48, No. 7, July, 2012)
SYNTHESIS AND REACTIVITY OF METHYL 3-ACYL-
6-AMINO-4-ARYL-5-CYANO-4H-PYRAN-2-CARBOXYLATES
V. P. Sheverdov1*, A. Yu. Andreev1, O. V. Ershov1, O. E. Nasakin1,
V. A. Tafeenko2, and V. L. Gein3
By treating arylidenemalononitriles with methyl 2,4-dioxobutanoates, derivatives of 4H-pyrans - methyl
3-acyl-6-amino-4-aryl-5-cyano-4H-pyran-2-carboxylates - are obtained, which are novel, promising
structural components for the synthesis of carbo- and heterocycles. The reactions of these pyrans with
sulfuric and hydrochloric acids, acetic anhydride, and alcohols have been studied. Novel methods have
been developed for the preparation of substituted derivatives of cyclopentenone, pyrano[2,3-d]-
pyrimidine, 5-oxo-3-phenylpentanoic acid, and nicotinic acid nitrile.
Keywords: cyclopentenones, 5-oxopentanoic acid, 4H-pyrans, pyridines, ring opening.
The synthesis of novel 4H-pyrans is a current problem in organic chemistry. Different classes of organic
compounds can be obtained on their basis. 4H-Pyrans, including 2-amino-3-cyano-4H-pyrans, exhibit
antimicrobial [1, 2], antiviral [3], analgesic [4], antitumor [5-8], fungicidal [9, 10], and herbicidal [11] activity.
We have used arylidenemalononitriles and methyl 2,4-dioxobutanoate in the synthesis of novel
2-amino-3-cyano-4H-pyrans. Methyl 2,4-dioxobutanoates have been used before in the synthesis of five- and
six-membered nitrogen-containing heterocycles [12-15]. The reactions of arylidenemalononitriles with these
esters have not been studied before.
R
Ar
2-PrOH
Morpholine (cat.)
35°C, 1 h
N
N
O
O
O
O
OMe
+
R
Ar
O
NH2
O
2a–d
N
OMe
1a–c
3a–f
1 a Ar = Ph, b Ar = 3-ClC6H4, c Ar = 2-ClC6H4; 2 a R = Me, b R = Ph, c R = 4-MeOC6H4,
d R = 4-MeC6H4; 3 a R = Me, Ar = Ph; b R = Ph, Ar = Ph; c R = 4-MeOC6H4, Ar = Ph;
d R = 4-MeC6H4, Ar = Ph; e R = Me, Ar = 3-ClC6H4; f R = 4-MeC6H4, Ar = 2-ClC6H4
_______
*To whom correspondence should be addressed, e-mail: SheverdovVP@yandex.ru.
1 Chuvashia State University named after I. N. Ulyanov, 15 Moscovsky Ave., Cheboksary 428015, Russia.
2M. V. Lomonosov Moscow State University, 1, Build. 3, Leninskie Gory, Moscow 119991, Russia; e-mail:
tafeenko-victor@yandex.ru.
3Perm' State Pharmaceutical Academy, 2 Polevaya St., Perm' 614990, Russia; e-mail: geinvl48@mail.ru.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1073-1082, July, 2012. Original
article submitted October 31, 2011.
0009-3122/12/4807-0997©2012 Springer Science+Business Media New York
997

We have used our previously discovered method for the preparation of methyl 3-acyl-6-amino-4-aryl-
5-cyano-4H-pyran-2-carboxylates [16] from arylidenemalononitriles and methyl 2,4-dioxobutanoates in propan-
2-ol in the presence of a catalytic amount of morpholine for the differently substituted starting compounds 1a-c and
2a-d.
The structure of the synthesized pyrans 3a-f was confirmed by the X-ray structural data for compound
3a (Fig. 1).
Fig. 1. Molecular structure of compound 3a with atoms represented by thermal vibration ellipsoids of 50%
probability.
This unique combination of different functional groups in the methyl 3-acyl-6-amino-4-aryl-5-cyano-
4H-pyran-2-carboxylates 3 and their susceptibility to ring opening gives them novel and unusual properties.
R
Ph
R
Ph
N
N
H2O
H2SO4
O
O
O
O
3a–c
+
Dioxane
O
O
NH2
OH NH2
OH
MeO
OMe
i1
i2
N
R
Ph
R
Ph
N
H2O
O
O
O
O
NH2
–MeOH
–NH3
–CO2
–H2O
OH
O O
O
O
OH
R
OMe
i4
i3
Ph
Ph
R
N
N
O
HO
O
O
OH
O
i5
4a–c
4 a R = Me, b R = Ph, c R = 4-MeOC6H4
998

We have found that heating the pyrans 3a-c for 4-6 h in a mixture of 10% aqueous H2SO4–dioxane
gives the cyclopentenones 4a-c. The structure of the cyclopentenones was confirmed from the X-ray structural
analysis of compound 4c (Fig. 2).
Fig. 2. Molecular structure of compound 4c with atoms represented by thermal vibration ellipsoids of 50%
probability.
We propose that water at first adds to the C=C double bond of the pyran ring. The following stages are:
opening of the ring in intermediate i1 to i2, hydrolysis of intermediate i3 to i4, dehydration, decarboxylation, and
cyclization of intermediate i4 to i5 to give the cyclopentenones 4a-c.
Novel methods for the synthesis of substituted cyclopentenones have a high value since the
cyclopentenone fragment is an important component in natural compounds and their analogs [17-19]. Known
routes for the formation of 3-oxo-2-hydroxycyclopentene-1-carbonitrile unit involve three stages with the use of
organometallic reagents and low temperatures, and the yields are low (16-22%) [19].
A high reactivity of the 4H-pyrans 3 is indicated by their reactions with acetic anhydride in the presence
of sulfuric acid. For example, heating compounds 3b,e to 80-90ºC for 1 min gives the pyrano[2,3-d]pyri-midines
5a,b. Similar known reactions of 4H-pyrans take 6-10 h [2].
R
Ar
O
Ac2O, H2SO4
O
O
NH
Me
3b,e
O
N
OMe
5a,b
5 a R = Ph, Ar = Ph; b R = Me, Ar = 3-ClC6H4
Different transformations occur when refluxing the pyrans 3b,c in concentrated hydrochloric acid over
12 h. Hydrolysis gives the acids 6a,b.
999

We propose that water initially adds to the pyran ring C=C bond to give the intermediate i1, which
opens to i2. It is likely that hydrolysis and decarboxylation of i3 then gives i4, followed by decarboxylation of
intermediate i4 to i5. The final stage is the hydrolysis of intermediate i5 to form the acids 6a,b.
R
Ph
R
Ph
R
Ph
N
N
N
HCl
H2O
O
O
O
O
O
3b,c
+
O
O
NH2
O
NH2
O
O
OH NH
OH
MeO
OMe
OMe
N
i1
i2
i3
R
Ph
N
R
Ph
H2O
–CO2
–MeOH
–NH3
O
HO
–CO2
O
OH
i5
O
O
i4
O
Ph
O
O
Ph
O
H2O
MeOH, H2SO4
(R = Ph)
OMe
–NH3
R
OH
6a,b
7
6 a R = Ph, b R = 4-MeOC6H4
In order to confirm the conversion of pyrans 3b,c to acids 6a,b, we carried out a reaction of the acid 6a
with methanol in the presence of sulfuric acid to give the ester 7. Synthesis of compounds 6a, 7 had been carried
out previously from 4-phenyldihydro-2H-pyran-2,6(3H)-dione [20]. However, this method is laborious,
involves the use of phenylmagnesium bromide, and needs cooling to -78ºC.
This more profound transformation of pyrans 3 to acids 6 occurs when using concentrated hydrochloric
acid (reaction time 12 h, acid concentration 35%), compared with the reaction of 3→4 (reaction time 4-6 h, acid
concentration 10%), and is likely due to the more forcing conditions.
Another route using the pyrans 3 as promising synthons is a reaction in the presence of a base. We have
found that short (1 min) heating of pyrans 3c,d in an alcohol (methanol, ethanol, or ethylene glycol) in the
presence of potassium hydroxide gives the pyridinecarbonitriles 8a-d.
R
Ph
R
Ph
N
N
R1OH
O
R1
R1OH, KOH
O
O
3c,d
+
O
O
R1
NH2
O
NH
i2
O
O
MeO
OMe
i1
R
Ph
Ph
Ph
N
N
N
O
R1
O
–MeO2CCO2R1
R1
R1
–H2O
O
R1
O
O
OH
R
R
N
O
NH
O
HN
OMe
i3
i4
8a–d
8 a R = 4-MeOC6H4, R1 = Me; b R = 4-MeOC6H4, R1 = C2H4OH;
c R = 4-MeC6H4, R1 = Me; d R = 4-MeC6H4, R1 = Et
1000

Evidently there initially occurs an addition of alcohol to the C=C double bond of the pyran ring. The
subsequent stages are: opening of the cyclic intermediate i1 to i2, addition of the alcohol to intermediate i2,
elimination of an oxalate ester from intermediate i3, cyclization and aromatization of intermediate i4 to the
nicotinic acid nitrile 8. Processes analogous to transformations of intermediate i4 to the pyridines 8 have been
described in study [21]. The reactions 3→8 that we have carried out represent a novel approach to the
preparation of nicotinic acid nitriles. The known method of preparing 2-alkoxynicotinic nitriles is more
laborious and lengthy [22].
Hence we have found that reactions of arylidenemalononitriles with methyl 2,4-dioxobutanoates give
the methyl 3-acyl-6-amino-4-aryl-5-cyano-4H-pyran-2-carboxylates, providing a novel route to highly reactive
pyrans. The ability of methyl 3-acyl-6-amino-4-aryl-5-cyano-4H-pyran-2-carboxylates to undergo ring opening
and also their diverse functionality are decisive factors in their single-stage transformations to substituted
cyclopentenones, pyran[2,3-d]pyrimidines, 5-oxopentanoic acids, and nicotinic acid nitriles. In fact, we propose
that these structures are the most reactive and promising synthons amongst known 4H-pyrans.
EXPERIMENTAL
IR spectra were recorded for a thin film of vaseline oil suspension on an FSM-1201 instrument. 1H and
13C NMR spectra were recorded on a Bruker DRX-500 (500 and 125 MHz, respectively) for DMSO-d6
solutions with TMS as internal standard. Mass spectra were recorded on a Finnigan MAT INCOS-50 instrument
(70 eV electron impact). Monitoring of the reaction course and the purity of the prepared compounds was
carried out by TLC on Silufol UV-254 plates, which were eluted with EtOAc and visualized with UV radiation,
iodine vapor, and also by thermal decomposition. Elemental analysis was carried out on a Carlo-Erba apparatus.
Melting points were determined with a capillary instrument.
Methyl 3-Acyl-6-amino-4-aryl-5-cyano-4H-pyran-2-carboxylates (3a-f) (General Method).
Morpholine (1 drop) was added to a mixture of arylidenemalononitrile 1a-c (1 mmol) and methyl 2,4-dioxo-
butanoate 2a-d (1 mmol) in 2-PrOH (8 ml). The reaction mixture was stirred for 1 h at 35ºC and maintained for
10-12 h at room temperature. The precipitate formed was filtered off, washed with a mixture of 2-PrOH and
hexane (1:1), and recrystallized from 2-PrOH.
Methyl 3-Acetyl-6-amino-5-cyano-4-phenyl-4H-pyran-2-carboxylate (3a). Yield 0.24 g (82%).
1
White crystals, mp 185-186ºC. IR spectrum, , cm-1: 3399, 3317, 2198, 1734, 1691, 1647, 1602. H NMR
spectrum, , ppm (J, Hz): 1.91 (3Н, s, СН3CO); 3.78 (3Н, s, СООСН3); 4.47 (1Н, s, СНPh); 7.11 (2Н, s, NH2);
7.19-7.21 (2Н, m, Н-2,6 Рh); 7.29-7.31 (1Н, m, H-4 Ph); 7.46-7.49 (2Н, m, H-3,5 Ph). Mass spectrum, m/z (Irel,
%): 298 [M]+ (21). Found, %: C 64.14; H 4.88; N 9.44. C16H14N2O4. Calculated, %: C 64.42; H 4.73; N 9.39.
Methyl 6-Amino-3-benzoyl-5-cyano-4-phenyl-4H-pyran-2-carboxylate (3b). Yield 0.31 g (87%).
1
White crystals, mp 184-185ºC. IR spectrum, , cm-1: 3428, 3310, 2197, 1733, 1658, 1642, 1593. H NMR
spectrum, , ppm (J, Hz): 3.47 (3Н, s, ОСН3); 4.43 (1Н, s, СНPh); 7.11-7.14 (2Н, m, H-2,6 Ph); 7.15-7.17 (1Н,
m, H-4 Ph); 7.19 (2Н, s, NH2); 7.22-7.25 (2Н, m, H-3,5 Ph); 7.36-7.39 (2Н, m, H-2,6 Ph); 7.53-7.55 (1Н, m,
H-4 Ph); 7.61-7.64 (2Н, m, H-3,5 Ph). Mass spectrum, m/z (Irel, %): 360 [M]+ (12). Found, %: C 70.15; H 4.31;
N 7.87. C21H16N2O4. Calculated, %: C 69.99; H 4.48; N 7.77.
Methyl 6-Amino-5-cyano-3-(4-methoxybenzoyl)-4-phenyl-4H-pyran-2-carboxylate (3c). Yield 0.33
1
g (85%). White crystals, mp 170-171ºC. IR spectrum, , cm-1: 3440, 3325, 2194, 1736, 1674, 1642, 1600. H
NMR spectrum, , ppm (J, Hz): 3.48 (3Н, s, СООСН3); 3.79 (3Н, s, СН3ОC6H4); 4.39 (1Н, s, СНPh); 6.91 (2Н,
d, J = 8.9, H-3,5 Ar); 7.11-7.14 (2Н, m, H Ph); 7.15 (2Н, s, NH2); 7.15-7.17 (1Н, m, H-4 Ph); 7.23-7.26 (2Н, m,
H Ph); 7.38 (2Н, d, J = 8.9, H-2,6 Ar). Mass spectrum, m/z (Irel, %): 390 [M]+ (5). Found, %: C 67.75; H 4.84;
N 7.02. C22H18N2O5. Calculated, %: C 67.69; H 4.65; N 7.18.
Methyl 6-Amino-5-cyano-3-(4-methylbenzoyl)-4-phenyl-4H-pyran-2-carboxylate (3d). Yield 0.30 g
(79%). White crystals, mp 160-161ºC. IR spectrum, , cm-1: 3402, 3327, 2197, 1737, 1676, 1648, 1602.
1001

1H NMR spectrum, , ppm (J, Hz): 2.32 (3Н, s, СН3C6H4); 3.46 (3Н, s, СООСН3); 4.31 (1Н, s, СНPh); 7.11
(2Н, d, J = 8.1, H-3,5 Ar); 7.11-7.14 (2Н, m, H Ph); 7.15-7.17 (1Н, m, H-4 Ph); 7.18 (2Н, s, NH2); 7.21-7.24
(2Н, m, H Ph); 8.01 (2Н, d, J = 8.1, H-2,6 Ar). Mass spectrum, m/z (Irel, %): 374 [M]+ (4). Found, %: C 70.97;
H 4.65; N 7.51. C22H18N2O4. Calculated, %: C 70.58; H 4.85; N 7.48.
Methyl 3-Acetyl-6-amino-4-(3-chlorophenyl)-5-cyano-4H-pyran-2-carboxylate (3e). Yield 0.24 g
1
(72%). White crystals, mp 150-151ºC. IR spectrum, , cm-1: 3455, 3294, 2176, 1692, 1671, 1634, 1595. H
NMR spectrum, , ppm (J, Hz): 2.01 (3Н, s, СН3CO); 3.78 (3Н, s, СООСН3); 4.54 (1Н, s, СНAr); 7.17 (2Н, s,
NH2); 7.18-7.20 (1Н, m, H Ar); 7.27 (1Н, s, H Ar); 7.37-7.39 (1Н, m, H Ar); 7.40-7.42 (1Н, m, H Ar). Mass
spectrum, m/z (Irel, %): 332 [M]+ (9). Found, %: C 57.63; H 4.02; N 8.29. C16H13ClN2O4. Calculated, %:
C 57.76; H 3.94; N 8.42.
Methyl 6-Amino-4-(2-chlorophenyl)-5-cyano-3-(4-methylbenzoyl)-4H-pyran-2-carboxylate (3f).
Yield 0.29 g (71%). White crystals, mp 210-211ºC. IR spectrum, , cm-1: 3409, 3324, 2196, 1657, 1600.
1H NMR spectrum, , ppm (J, Hz): 2.33 (3Н, s, СН3C6H4); 3.78 (3Н, s, ОСН3); 4.59 (1Н, s, СНAr); 7.15 (2Н, s,
NH2); 7.13-7.15 (2Н, m, H Ar); 7.17-7.19 (1Н, m, H Ar); 7.19-7.21 (2Н, m, H Ar); 7.22-7.24 (1Н, m, H Ar);
7.33-7.35 (1Н, m, H Ar); 7.38-7.40 (1Н, m, H Ar). Mass spectrum, m/z (Irel, %): 408 [M]+ (7). Found, %:
C 64.69; H 4.12; N 6.94. C22H17ClN2O4. Calculated, %: C 64.63; H 4.19; N 6.85.
2-Hydroxy-4-[hydroxy(R)methylene]-3-oxo-5-phenylcyclopent-1-enecarbonitriles (4a-c) (General
Method). A mixture of the pyran 3a-c (1 mmol), water (30 ml), conc. H2SO4 (1.8 ml), and dioxane (1 ml) was
heated for 4-6 h. After cooling to room temperature the mixture was diluted with water (20 ml) and left for 24 h.
The precipitate formed was washed with water (225 ml) and dissolved in EtOAc (15 ml). The ethyl acetate
layer was dried over MgSO4 and evaporated in vacuo. The residue was separated on a silica gel column eluting
with a mixture of EtOAc and hexane (3:1).
2-Hydroxy-4-(1-hydroxyethylidene)-3-oxo-5-phenylcyclopent-1-enecarbonitrile (4a). Yield 0.067 g
1
(28%). Yellow crystals, mp 179-180ºC. IR spectrum, , cm-1: 3435, 3205, 2222, 1650, 1638, 1603. H NMR
spectrum, , ppm (J, Hz): 2.03 (3Н, s, СН3); 4.92 (1Н, s, СНPh); 7.19-7.22 (2Н, m, H-3,5 Ph); 7.37-7.40 (2Н,
m, H-2,6 Ph); 7.40-7.42 (1Н, m, H-4 Ph); 12.56 (2Н, br. s, ОH). Mass spectrum, m/z (Irel, %): 241 [M]+ (12).
Found, %: C 69.42; H 4.67; N 5.96. C14H11NO3. Calculated, %: C 69.70; H 4.60; N 5.81.
2-Hydroxy-4-[hydroxy(phenyl)methylene]-3-oxo-5-phenylcyclopent-1-enecarbonitrile (4b). Yield
0.12 g (41%). Yellow crystals, mp 172-173ºC. IR spectrum, , cm-1: 3410, 3250, 2211, 1664, 1640, 1596.
1H NMR spectrum, , ppm (J, Hz): 4.90 (1Н, s, СНPh); 7.23-7.52 (10Н, m, H Ph); 12.76 (2Н, br. s, ОH). Mass
spectrum, m/z (Irel, %): 303 [M]+ (17). Found, %: C 75.52; H 4.39; N 4.51. C19H13NO3. Calculated, %: C 75.24;
H 4.32; N 4.62.
2-Hydroxy-4-[hydroxy(4-methoxyphenyl)methylene]-3-oxo-5-phenylcyclopent-1-enecarbonitrile
(4c). Yield 0.14 g (43%). Yellow crystals, mp 169-170ºC. IR spectrum, , cm-1: 3440, 3250, 2209, 1670, 1640,
1
1610. H NMR spectrum, , ppm (J, Hz): 3.79 (3Н, s, СН3); 4.87 (1Н, s, СНAr); 7.23-7.39 (9Н, m, H Ar);
12.76 (2Н, br. s, ОH). Mass spectrum, m/z (Irel, %): 333 [M]+ (11). Found, %: C 72.36; H 4.42; N 4.07.
C20H15NO4. Calculated, %: C 72.06; H 4.54; N 4.20.
Methyl
6-Acyl-5-aryl-2-methyl-4-oxo-4,5-dihydro-3H-pyrano[2,3-d]pyrimidine-7-carboxylates
5a,b (General Method). The pyran 3b,e (1 mmol), Ac2O (1.5 ml), and conc. H2SO4 (15 mg, 0.15 mmol) were
mixed. The reaction mixture was heated for 1 min at 80-90ºC, cooled to room temperature, and water (2 ml) was
added. After 24 h the residue was filteredb off and washed with water (10 ml) and a 1:1 mixture of 2-PrOH and
hexane (5 ml). The product was recrystallized from 2-PrOH.
Methyl
6-Benzoyl-2-methyl-4-oxo-5-phenyl-3,5-dihydro-4H-pyrano[2,3-d]pyrimidine-7-carb-
oxylate (5a). Yield 0.37 g (91%). White crystals, mp 255-256ºC. IR spectrum, , cm-1: 3200, 1738, 1668, 1642,
1
1596. H NMR spectrum, , ppm (J, Hz): 2.30 (3Н, s, 2-СН3); 3.51 (3Н, s, СООСН3); 4.69 (1Н, s, СНPh);
7.09-7.12 (2Н, m, Н-2,6 Ph); 7.13-7.15 (1Н, m, Н-4 Ph); 7.20-7.23 (2Н, m, Н-3,5 Ph); 7.37-7.40 (2Н, m, Н-2,6
Ph); 7.54-7.56 (1Н, m, Н-4 Ph); 7.62-7.65 (2Н, m, Н-3,5 Ph); 12.64 (1H, s, NH). Mass spectrum, m/z (Irel, %):
402 [M]+ (13). Found, %: C 68.39; H 4.58; N 6.78. C23H18N2O5. Calculated, %: C 68.65; H 4.51; N 6.96.
1002

Methyl
6-Acetyl-5-(3-chlorophenyl)-2-methyl-4-oxo-3,5-dihydro-4H-pyrano[2,3-d]pyrimidine-
7-carboxylate (5b). Yield 0.33 g (87%). White crystals, mp 221-222ºC. IR spectrum, , cm-1: 3150, 1727,
1
1706, 1669, 1644, 1598. H NMR spectrum, , ppm (J, Hz): 2.02 (3Н, s, СН3CO); 2.28 (3Н, s, 2-СН3); 3.81
(3Н, s, СООСН3); 4.79 (1Н, s, СНAr); 7.20-7.22 (1Н, m, H Ar); 7.30 (1Н, s, H Ar); 7.31-7.33 (1Н, m, H Ar);
7.34-7.36 (1Н, m, H Ar); 12.64 (1H, s, NH). Mass spectrum, m/z (Irel, %): 374 [M]+ (9). Found, %: C 57.80;
H 4.16; N 7.38. C18H15ClN2O5. Calculated, %: C 57.69; H 4.03; N 7.47.
5-Aryl-5-oxo-3-phenylpentanoic Acids (6a,b) (General Method). Conc. HCl (10 ml) was added to
the pyran 3b,c (0.5 mmol) and refluxed for 12 h. The precipitate formed was washed with a 1:1 mixture of
2-PrOH and hexane and recrystallized from 2-PrOH.
5-Oxo-3,5-diphenylpentanoic Acid (6a). Yield 97 mg (72%). White crystals, mp 126-128ºC. IR
1
spectrum, , cm-1: 1697, 1679, 1670. H NMR spectrum, , ppm (J, Hz): 2.56 (1H, dd, J = 15.8, J = 8.6) and
2.70 (1H, dd, J = 15.8, J = 6.4, CH2СOOH); 3.37 (1H, dd, J = 11.1, J = 6.4) and 3.45 (1H, dd, J = 11.1, J = 7.8,
PhCOCH2); 3.65-3.67 (1Н, m, CHPh); 7.13-7.15 (1Н, m, H Ph); 7.23-7.25 (2Н, m, H Ph); 7.28-7.31 (2Н, m,
H Ph); 7.48-7.50 (2Н, m, H Ph); 7.60-7.62 (1Н, m, H Ph); 7.91-7.93 (2Н, m, H Ph); 12.06 (1H, s, COOH).
Mass spectrum, m/z (Irel, %): 268 [M]+ (21). Found, %: C 76.15; H 6.04. C17H16O3. Calculated, %: C 76.10;
H 6.01.
5-(4-Methoxyphenyl)-5-oxo-3-phenylpentanoic Acid (6b). Yield 100 mg (70%). White crystals, mp
1
153-155ºC. IR spectrum, , cm-1: 1698, 1672, 1602, 1505. H NMR spectrum, , ppm (J, Hz): 2.55 (1H, dd,
J = 15.8, J = 8.6) and 2.68 (1H, dd, J = 15.8, J = 6.3, CH2СOOH); 3.28 (1H, dd, J = 16.7, J = 6.3) and 3.38 (1H,
dd, J = 16.7, J = 7.9, ArCOCH2); 3.63-3.65 (1Н, m, CHPh); 3.82 (3Н, s, ОСН3); 6.99-7.02 (2Н, m, H Ar);
7.13-7.15 (1Н, m, H Ph); 7.23-7.25 (2Н, m, H Ph); 7.29-7.31 (2Н, m, H Ph); 7.89-7.91 (2Н, m, H Ar); 12.02
(1H, s, COOH). Mass spectrum, m/z (Irel, %): 298 [M]+ (15). Found, %: C 72.44; H 6.03. C18H18O4. Calculated,
%: C 72.47; H 6.08.
Methyl 5-Oxo-3,5-diphenylpentanoate (7). One drop of conc. H2SO4 was added to a solution of
5-oxo-3,5-diphenylpentanoic acid (6a) (1.34 g, 5 mmol) in MeOH (15 ml) and refluxed for 8 h. Water (15 ml)
was added. The white precipitate obtained was filtered off, washed with water, and recrystallized from a 1:1
mixture of 2-PrOH and hexane. Yield 1.07 g (76%). White crystals, mp 73-75ºC. IR spectrum, , cm-1: 1730,
1679, 1598. 1H NMR spectrum, , ppm (J, Hz): 2.62 (1H, dd, J = 15.3, J = 7.3) and 2.80 (1H, dd, J = 15.3, J = 7.3,
CH2СOOMe); 3.36 (1H, dd, J = 16.7, J = 6.9) and 3.41 (1H, dd, J = 16.7, J = 6.9, PhCOCH2); 3.59 (3H, s,
СООCH3); 3.75-3.76 (1Н, m, CHPh); 7.13-7.15 (1Н, m, H Ph); 7.25-7.28 (2Н, m, H Ph); 7.28-7.30 (2Н, m,
H Ph); 7.50-7.52 (2Н, m, H Ph); 7.61-7.63 (1Н, m, H Ph); 7.90-7.92 (2Н, m, H Ph). Mass spectrum, m/z (Irel,
%): 282 [M]+ (33). Found, %: C 76.61; H 6.47. C18H18O3. Calculated, %: C 76.57; H 6.43.
2-Alkoxy-4,6-diaryl-3-pyridinecarbonitriles (8a-d) (General Method). The pyran 3c,d (1 mmol) was
added to a solution of potassium hydroxide (0.2 g, 3.5 mmol) in an alcohol (methanol, ethanol, or ethylene
glycol) (10 ml) and heated for 1 min at 64ºC. The mixture was cooled to room temperature, diluted with water
(20 ml), and neutralized with 10% HCl to pH 7. The precipitate formed was filtered off, washed with water
(225 ml), and recrystallized from 2-PrOH (compounds 8a,c) or from a 1:1 mixture of 2-PrOH and hexane
(compounds 8b,d).
2-Methoxy-6-(4-methoxyphenyl)-4-phenylnicotinonitrile (8a). Yield 0.25 g (78%). White crystals,
1
mp 145-146ºC. IR spectrum, , cm-1: 2220, 1583, 1549. H NMR spectrum, , ppm (J, Hz): 3.83 (3H, s,
CH3OC6H4); 4.14 (3H, s, 2-ОCH3); 7.19 (2Н, d, J = 8.8, H-3,5 Ar); 7.57-7.60 (3H, m, Н-3,4,5 Ph); 7.63 (2H, m,
H-2,6 Ph); 7.65 (1H, s, H-5); 8.24 (2Н, d, J = 8.8, H-2,6 Ar). 13C NMR spectrum, , ppm: 54.4; 55.5; 91.2;
112.8; 114.3; 115.6; 128.6; 128.9; 129.1; 129.2; 130.0; 136.0; 156.2; 157.2; 161.5; 164.3. Mass spectrum, m/z
(Irel, %): 316 [M]+ (78). Found, %: C 76.22; H 5.19; N 8.75. C20H16N2O2. Calculated, %: C 75.93; H 5.10;
N 8.85.
2-(2-Hydroxyethoxy)-6-(4-methoxyphenyl)-4-phenylnicotinonitrile (8b). Yield 0.25 g (71%). White
crystals, mp 190-191ºC. IR spectrum, , cm-1: 3306, 2214, 1683, 1642. 1H NMR spectrum, , ppm (J, Hz): 3.58
(2H, d, J = 6.9, CH2OH); 3.64 (1H, s, OH); 3.83 (3H, s, CH3OC6H4); 4.37 (2H, d, J = 6.9, 2-OCH2); 7.18 (2Н,
1003

d, J = 8.8, H-3,5 Ar); 7.57-7.59 (3H, m, H-3,4,5 Ph); 7.63-7.64 (2H, m, H-2,6 Ph); 7.64 (1H, s, H-5); 8.21 (2Н,
d, J = 8.8, H-2,6 Ar). 13C NMR spectrum, , ppm: 55.5; 60.0; 71.1; 91.2; 112.8; 114.4; 115.4; 128.4; 128.9;
129.1; 129.2; 130.1; 136.0; 156.2; 157.2; 161.5; 165.0. Mass spectrum, m/z (Irel, %): 346 [M]+ (51). Found, %:
C 72.59; H 5.12; N 7.97. C21H18N2O3. Calculated, %: C 72.82; H 5.24; N 8.09.
2-Methoxy-6-(4-methylphenyl)-4-phenylnicotinonitrile (8c). Yield 0.24 g (81%). White crystals, mp
1
159-160ºC. IR spectrum, , cm-1: 2221, 1677, 1588, 1546. H NMR spectrum, , ppm (J, Hz): 2.39 (3H, s,
CH3C6H4); 4.17 (3H, s, 2-OCH3); 7.36 (2Н, d, J = 8.1, H-3,5 Ar); 7.58-7.61 (3H, m, H-3,4,5 Ph); 7.74-7.75 (2H,
m, H-2,6 Ph); 7.79 (1H, s, H-5); 8.19 (2Н, d, J = 8.1, Н-2,6 Ar). 13C NMR spectrum, , ppm: 21.3; 54.5; 91.6;
112.9; 114.4; 124.2; 127.2; 128.8; 129.0; 129.3; 130.6; 136.1; 138.5; 156.3; 157.3; 164.5. Mass spectrum, m/z
(Irel, %): 300 [M]+ (100). Found, %: C 80.02; H 5.49; N 9.24. C20H16N2O. Calculated, %: C 79.98; H 5.37;
N 9.33.
2-Ethoxy-6-(4-methylphenyl)-4-phenylnicotinonitrile (8d). Yield 0.25 g (79%). White crystals, mp
1
150-151ºC. IR spectrum, , cm-1: 2222, 1674, 1588, 1544. H NMR spectrum, , ppm (J, Hz): 1.45 (3H, t,
J = 7.1, ОCH2CH3); 2.39 (3H, s, CH3C6H4); 4.64 (2H, q, J = 7.1, ОСH2CH3); 7.35 (2Н, d, J = 8.1, H-3,5 Ar);
7.56-7.59 (3H, m, H-3,4,5 Ph); 7.73-7.75 (2H, m, H-2,6 Ph); 7.75 (1H, s, H-5); 8.15 (2Н, d, J = 8.1, H-2,6 Ar).
13C NMR spectrum, , ppm: 14.9; 21.3; 63.4; 91.7; 112.9; 114.4; 124.2; 127.9; 128.8; 129.1; 129.6; 130.6;
136.1; 138.4; 156.3; 157.3; 164.2. Mass spectrum, m/z (Irel, %): 314 [M]+ (100). Found, %: C 80.33; H 5.82;
N 9.01. C21H18N2O. Calculated, %: C 80.23; H 5.77; N 8.91.
X-ray Structural Study of Compounds 3a and 4c. Crystals of compounds 3a and 4c were grown for
the X-ray structural analysis by evaporation from acetonitrile at room temperature. The diffraction data was
gathered at room temperature (295(2) K) on a CAD-4 diffractometer with graphite monochromator, MoK
radiation, and -scanning. The standard WinGX procedure was used for data processing [23]. Control
measurements were taken every 120 min. Correction for absorption was not performed. The structures of the
compounds were analyzed by a direct method and refined using the SHELX software [24]. The refinement of
the positional and thermal parameters for the non-hydrogen atoms was carried out in a full-matrix, anisotropic
approximation. Hydrogen atoms were localized by Fourier difference synthesis and refined in the isotropic
approximation. Thermal parameters for the hydrogen atoms occurred in the range of 0.054-0.126 and 0.036-
0.103 Å2 for compounds 3a and 4c, respectively. R factors, calculated for F2 > 2(F2), were 0.045 (2140
reflections) for compound 3a and 0.044 (2850 reflections) for the compound 4c. The images for the molecular
structures were prepared using the DIAMOND software [25].
X-ray crystallographic data for compound 3a: C16H14N2O4. M 298.29, triclinic symmetry. Unit cell
parameters: a 7.194(2), b 10.090(1), c 11.075(2) Å,  105.74,  94.63,  75.05(2)º, V 747.5(3) Å3; space group
P-1; Z 2; dcalc 1.325 g·cm-3; (MoK) 0.097; 2926 reflections gathered, of which 2140 had I > 2(I); probability
factor R 0.045.
X-ray crystallographic data for compound 4c: C20H15NO4. M 333.33, triclinic symmetry. Unit cell
parameters: a 9.5147(12), b 10.0778(14), c 9.5877(13) Å,  91.01,  81.52,  113.13(2)º, V 835.3(2) Å3; space
group P-1; Z 2; dcalc 1.325 g·cm-3; (MoK) 0.092; 4020 reflections gathered, of which 2850 had I > 2(I);
probability factor R 0.044.
The crystallographic data has been submitted to the Cambridge Crystallographic Data Center (deposit
CCDC-764770 for compound 3a and CCDC-764769 for compound 4c).
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