Recyclization of 1,4-dihydropyridine derivatives in acidic medium

Article abstract of DOI:10.1007/s10593-007-0006-0

The recyclization of 1,4-dihydropyridines in aqueous-alcoholic hydrochloric acid medium proceeds with cleavage of a C-N bond and pyridine ring opening. Cyclohexenone derivatives are formed as a result of the subsequent intramolecular crotonic condensation of the acyclic intermediate. The leaving carbonyl substituents depart simultaneously with recyclization, depending on the acidity of the reaction medium.

Full text of DOI:10.1007/s10593-007-0006-0

Chemistry of Heterocyclic Compounds, Vol. 43, No. 1, 2007
RECYCLIZATION OF 1,4-DIHYDROPYRIDINE
DERIVATIVES IN ACIDIC MEDIUM
S. Stupnikova, E. Petushkova, D. Muceniece, and V. Lūsis
The recyclization of 1,4-dihydropyridines in aqueous-alcoholic hydrochloric acid medium proceeds with
cleavage of a C-N bond and pyridine ring opening. Cyclohexenone derivatives are formed as a result of
the subsequent intramolecular crotonic condensation of the acyclic intermediate. The leaving carbonyl
substituents depart simultaneously with recyclization, depending on the acidity of the reaction medium.
Keywords: 1,4-dihydropyridines, cyclohex-2-enones, recyclization, hydrolysis of enamines, elimination
of carbonyl substituents.
The recyclization of dihydropyridines (DHP) in acidic medium, leading to the formation of
cyclohexenone derivatives, has been recommended [1] for obtaining these difficultly available compounds, and
is frequently used in the organic synthesis, although yields of them did not exceed 30%. 1,5-Diketones are
intermediates of 1,4-DHP transformation and can be also the target products [2-4]. The conversion of certain
readily available ethyl 4-phenyl-1,4-dihydropyridine-3,5-dicarboxylates into derivatives of cyclohex-2-enones
by the action of hydrochloric acid in aqueous alcoholic medium has been described previously [5].
In the present work the recyclization of 1,4-DHP with differing substituents in positions 3 and 5 has
been studied. The character of the 3- and 5-substituents of DHP has a strong influence on the DHP ring opening
ability, on the tendency towards elimination of these functions under recyclization conditions, and also on the
formation of cyclohexenone regioisomers.
Ring opening of dihydropyridines in acidic medium takes place as the hydrolysis of enamines
comprising three separate stages: 1) protonation of the enamine, leading to an immonium ion; 2) addition of
water forming a hydroxy amine; 3) elimination of amine.
It is generally accepted that in acidic medium the rate limiting step is elimination of amine [6].
Hydrolysis is preceded by the equilibrium protonation stage (equilibrium of enamine – immonium ion), which
depends on the acidity of the medium and the basicity of the enamine.
_______
* Dedicated to Prof. Dr. E. Lukevics on the occasion of his 70th birthday.
To respected scientist and dependable friend. The instant in which we live is the most significant.
Nobody is able to stop the moment, and risks only to make a mark.
__________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga, LV-1006, Latvia; e-mail: lusis@osi.lv, e-mail:
stupnikova@osi.lv, e-mail: muceniece@osi.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1,
pp. 49-58, January, 2007. Original article submitted September 6, 2006.
0009-3122/07/4301-0041©2007 Springer Science+Business Media, Inc.
41

R
R
R
R2
H
R2
H
R1
R2
R1
R1
+
H
H2O
Me
+
N
N
Me
Me
N
Me
Me
Me
OH
Me
Me
Me
R
R
R
R1
R2
O
R1
R2
O
R1
R2
O
H2O
+
– MeNH3
Me
Me
Me
O
NH
Me
Me
Me
B
A
The hydrolysis of DHP enamine fragment includes a cleavage of the N-C(2) bond and subsequent
elimination of amine from the resulting acyclic intermediate A leading to the pentane-2,6-dione derivative B.
The latter affords the cyclohexenone derivative upon intramolecular condensation of the terminal methyl group
with a carbonyl function.
In strongly acidic medium (2.4 M HCl) recyclization of 1,4-DHP 1a-f resulted in the formation of
cyclohexenones 2b-f in 54-84% yield. Under the reaction conditions elimination of both carbonyl functions of
the DHP occurs, consequently the same cyclohexenone 2b is formed either from DHP 1a or 1b.
R1
R1
R
R
2.4 M HCl
EtOH/H2O, 30 h
Me
N
Me
Me
O
Me
2b–f
1a–f
1 a, f R = Ac, b–e R = COOEt; 1a, b, 2 b R1 = Me;
1, 2 c R1 = Et, d R1 = Pr, e R1 = i-Pr, f R1 = Ph
If DHP 1f is subjected to hydrolysis under the action of acid of a lower concentration the acetyl
derivatives 3 and 4 are formed together with cyclohexenone 2f.
Ph
Ph
Ph
Ac
Ac
Ac
Ac
Ac
1.5 M HCl
2f
(30%)
+
+
EtOH/H2O, 8 h
Me
N
Me
Me
O
Me
OH
4
Me
3
1f
The ester group of a 1,4-DHP is comparatively stable under mild reaction conditions and a complex
mixture of recyclization products is isolated from the reaction mixture of DHP 1g,h acidic hydrolysis.
42

R1
R1
R1
R
R
R
R
O
R
R
0.6 M HCl
+
+
EtOH/H2O, 10 h
Me
OH
Me
Me
N
Me
Me
5g,h
6g,h
1g,h
R1
R1
R1
R1
R
R
R
R
R
R
+
+
+
+
Me
O
O
Me
O
Me
O
Me
7g,h
9g,h
10g,h
8g,h
1, 5–10 R = COOEt, g R1 = Et, h R1 = Pr
The acetyl substituent proved to be the more labile on cleavage of the unsymmetrical DHP (R ≠ R2) in a
medium of 1.0-1.8 M HCl in aqueous alcoholic solution. The recyclization of ethyl 5-acetyl-
1,4-dihydropyridine-3-carboxylates 1i,j resulted in formation of regio- and stereoisomeric esters of
cyclohexenonecarboxylic acids 8g,h, 9g,h, 11i,j, and 12i,j in addition to alkylcyclohexenes 2c,d.
R1
R1
R1
R2
R
R
R
1.0−1.8 M HCl
+
+
EtOH/H2O
Me
N
Me
Me
O
Me
O
Me
1i–k
8g,h
9g,h,k
2c,d
R1
R1
R
R
+
+
+
Me
O
Me
O
12i,j
11i–k
1 i–k R = COOEt; i R1 = Et, j R1 = Pr, k R1 = Ph; i–k R2 = Ac;
8g, 9g, 11i, 12i R = COOEt, R1 = Et; 8h, 9h, 11j, 12j R =COOEt, R1 = Pr;
9k, 11k R = COOEt, R1 = Ph
The occurrence of different cyclohexenone regioisomers is caused by the ability of both terminal methyl
groups of the intermediate B (R ≠ R1) to recyclization, and the formation of different diastereomers of these
isomers depends on the proton attack to the DHP ring: whether from the side of the 4-substituent or from the
opposite one.
In contrast to the above compounds 1i,j, the acidic recyclization of DHP 1k proceeds with the formation
of only two regioisomers 9k and 11k.
43

On recyclizing DHP 1l in strongly acidic medium, apart from cyanocyclohexenone 13, pyridine 14 was
isolated as a side product. In the course of recyclization the COOEt group is subject to elimination exclusively. It
has therefore been established that the DHP substituents at positions 3 and/or 5 can be arranged in the series Ac
> COOEt > CN in tendency to be split off.
Ph
Ph
Ph
CN
O
NC
Me
COOEt
Me
NC
Me
6 M HCl
+
EtOH/H2O
Me
N
H
N
Me
1l
14
13
The structures of all obtained compounds were established by NMR spectroscopy. The interaction
observed in the gHMBC spectrum of the H-4 proton with the C=C carbon atoms of cyclohexenone 3, (chemical
shifts 156.5 and 129.1 ppm respectively) and the CO group of the acetyl function (207.9 ppm) demonstrate that
the Ac substituent is located at the C-4 atom of cyclohexenone 3. The coupling constant J4,5 = 8.9 Hz indicates a
trans disposition of these protons.
The NOESY spectrum of compound 3 showed an intramolecular Overhauser effect between proton H-4
(3.76 ppm) and one of the protons at C-6 (2.66 ppm) that is possible only if these protons are disposed axially, and
the acetyl group equatorially. This is feasible only in the case when both bulky substituents (Ac and Ph) are situated
equatorially.
1
In the H NMR spectrum of 1,5-diacetyl-2-hydroxy-4-methyl-6-phenylcyclohexa-1,3-diene (4) the signal
of the acetyl group located at the C-1 atom is shifted upfield than the signal of the other C=O group (1.94 and
2.27 ppm). In the 13C NMR spectrum of enol 4 no signal is attributable to CO group (in ketone 3 the
corresponding signal is at 194.0 ppm). At the same time the signal present at 180 ppm corresponds to hydroxyl-
bearing olefinic carbon, which also confirms the structure of diene 4. The coupling constant J5,6 = 1.1 Hz
indicates the cis disposition of the 5-COCH3 and 6-C6H5 substituents.
The structures of compounds 5g,h and 10g,h (Table 1) were established by comparison of their NMR
spectra with the spectra of the known diastereomers of 4,6-dimethoxycarbonyl-3-methyl-5-phenyl-cyclohex-
2-enones [7].
Chromatography of the mixture of products obtained on hydrolysis of DHP 1i,j gave individual
regioisomers, each of which was a mixture of two diastereomers 8, 9 and 11, 12. Assignment of these
compounds to the series of derivatives of 2-oxocyclohex-3-ene- and 4-oxocyclohex-2-enecarboxylic acids was
made by analysis of NMR spectra (Table 2). Interaction of the ring proton with the ester group, observed in the
gHMBC spectra of all four isomers, enables to recognize the signal of H-1 correctly. Interaction of the
cyclohexenone proton H-1 with a carbon atom of the C=C bond (8, 9), or with the carbon atom of the 2-C=O
group (11, 12) enables the regioisomers to be identified. The coupling constants of the H-1 and H-6 protons
J = 10.9 and J = 5.4 Hz confirmed a trans (11) or cis (12) position of the ester group and the alkyl substituent of
the isomers. Diastereomers 8 and 9 also differ in the spatial disposition of the 1-COOEt and 6-alkyl substituents.
The spectral characteristics of compounds 8g and 9g are in agreement with the data of [8], where they are
described as an unresolvable mixture of isomers.
The trans disposition of the 1- and 6-substituents in cyclohexenone 13 was also established by 1H NMR.
For comparing the reactivity of the various DHP the rate constants of ring opening were determined in a
medium of 50% aqueous ethanolic hydrochloric acid. The acidity of reaction medium was characterized with
Hammett function according to [9].
44

TABLE 1. 1H NMR Spectra of the Synthesized Compounds 5-7, 10
Com-
pound
Chemical shifts, δ, ppm. (SSCC, J, Hz)*
Н-1
Н-2
Н-3
Н-5
5g
6g
3.19
(d, J = 11.6)
3.07-3.19 (m)
2.93 (d, J = 8.5)
5.87 (m)
2.83
3.47
—
5.97 (m)
(d, J = 0.9)
3.78 (s)
(dt, J = 0.9, J = 7.5)
2.54 (m)
7g
3.13 (d, J = 11.3)
3.43 (d, J = 5.0)
6.01 (m)
6.01 (m)
10g
3.76
2.57 (m)
(d, J = 13.0)
3.13
5h
3.06-3.13(m)
2.77 (d, J = 8.0)
5.79 (m)
(d, J = 11.6)
2.72 (s)
6h
7h
3.50 (t, J = 7.6)
—
3.13
5.91 (m)
5.93 (m)
3.71 (s)
2.60 (m)
(d, J = 11.3)
3.35 (d, J = 5.1)
10h
3.70 (d, J = 13.2)
2.62 (m)
5.95 (s)
_______
*The spectra of compounds were recorded in C6D6 at 600 MHz (5h-7h);
CDCl3 at 400 MHz (10h); C6D6 at 400 MHz (5g-7g); CDCl3 at 200 MHz
(10g, 7g).
TABLE 2. 1H NMR Spectra of the Synthesized Compounds 8h, 9h, 11i,j, 12i,j
Com-
pound
Chemical shifts, δ, ppm (SSCC, J, Hz)*
Н-1
Н-3
5-CН2
Н-6, m
11i
12i
8h
2.93 (d, J = 12.1)
5.75 (m)
0.57-1.44 (1Н, m);
1.69 (dd, J = 5.3, J = 18.0)
2.24
3.46 (d, J = 4.9)
3.08 (d, J = 6.3)
3.21 (d, J = 5.1)
3.00 (d, J = 10.9)
3.29 (d, J = 5.4)
5.91 (m)
5.95 (m)
5.94 (m)
5.82 (s)
5.82 (s)
0.57-1.44 (1Н, m);
1.69 (d.d, J = 5.3, J = 18.0)
2.24
2.45
2.12 (1Н, dd, J = 8.5, J = 16.4);
2.62 (1Н, dd, J = 4.7, J = 16.4)
9h
2.31 (1Н, dd, J = 4.4, J = 16.4);
2.59 (1Н, dd, J = 3.2, J = 16.4)
2.27
11j
12j
2.00 (1Н, dd, J = 11.0,
J = 18.0); 2.36-2.42 (1Н, m)
2.36-2.42
2.19
2.12 (1Н, dd, J = 5.0, J = 18.0);
2.36-2.42 (1Н, m)
_______
*Spectra of compounds were obtained in C6D6 at 200 MHz (11i, 12i)
and CDCl3 at 600 MHz (11j, 12j, 8h, 9h).
The measurements showed that for ring opening of N-unsubstituted DHP a substantially higher acidity
of the reaction medium is required than for hydrolysis of N-substituted 1,4-DHP (Fig. 1). 3- and 5-Substituents
of the starting DHP have a significant effect on the DHP ring opening: the acidity of the medium required for
hydrolysis grows in the series of substituents Ac < COOEt < CN.
45

Introduction at the nitrogen atom of a substituent (4-MeOC6H4) more electron-donating than Me has an
insignificant effect on the rate of DHP ring opening.
a
k·10-3, s-1
(5.8)
(4,9)
(4.0)
(3.1)
(2.1)
(1.3)
(0.62) (0.14)
H0(MHCl
)
b
k·10-3, s-1
(0.62)
(0.14)
(0490)
(0.029)
(0.0099)
(0.0035)
H0(MHCl
)
Fig. 1. The rate dependence of dihydropyridine ring opening on the acidity of medium:
а: 1 – R1 = R2 = Ac; 2 – R1 = R2 = COOEt; 3 – 1l; b: 1 – R = Me, R1 = R2 = COOEt; 2 – 1f;
3 – R = Ph, R1 = R2 = COOEt; 4 – R = 4-MeOPh, R1 = R2 = COOEt; 5 – R =Me, R1 = CN, R2 = COOEt
EXPERIMENTAL
The 1H, 13C, gHMBC, and (H, H)-NOESY NMR spectra were recorded on Varian Mercury 200, Varian
Mercury 400, and Varian-Inova 600 spectrometers (signals were referred to TMS). The IR spectra were taken on
a IR Prestige 21 spectrometer in KBr discs. The mass spectra were obtained on a HP 6890 GCMS spectrometer,
ionization energy 70 eV. The UV spectra were recorded on a Specord UV-VIS spectrometer.
The previously unknown 1,4-DHP 1i,j were synthesized by the method of [10]. N-Alkylation was
carried out analogously to [11].
46

Recyclization of 1,4-Dihydropyridines 1a-f under the Action of 2.4 M HCl (general procedure).
A solution of 1,4-DHP 1 (3 mmol) and conc. HCl (4.4 ml: 46 mmol) in 80% ethanol (15 ml) was refluxed for 30
h, then cooled to room temperature, diluted with water (20 ml), and extracted with CH2Cl2 (4×25 ml). The
combined extracts were dried and evaporated in vacuum. The yellow oil obtained was chromatographed
(hexane – t-butyl methyl ether (TBME), 2 : 1, silica gel) and 5-alkyl-3-methylcyclohexenones 2 were isolated.
The previously known dicyclohexenones 2b,e,f, obtained after recyclization in yields of 54 (from 1a)
or 74 (from 1b), 83, and 68% respectively, corresponded in all characteristics with the data of [12-14].
5-Ethyl-3-methylcyclohex-2-enone (2c). Yield 0.33 g (79%). IR spectrum, ν, cm-1: 1667 (C=O).
1H NMR spectrum (200 MHz, CDCl3), δ, ppm (J, Hz): 0.93 (3H, t, J = 7.3, CH2CH3); 1.41 (2H, m, CH2CH3);
1.93-2.12 (6H, m, 3-CH3, 4-CH2, 5-CH); 2.24-2.52 (2H, m, 6-CH2); 5,87 (1H, m, 2-CH). Mass spectrum,
m/z, (Irel, %): 138 (20) [M]+, 110 (3), 82 (100), 77 (2.4), 67 (3.8), 54 (9.6), 43 (2.4), 39 (9.6).
3-Methyl-5-propylcyclohex-2-enone (2d). Yield 0.38 g (84%). Bp 60°C (1.2 mbar). IR spectrum,
1
ν, cm-1: 1669 (C=O). H NMR spectrum (200 MHz, CDCl3), δ, ppm: 0.91 (3H, m, 5-(CH2)2CH3); 1.35 (4H, m,
5-(CH2)2CH3); 1.92-2.51 (8H, m, 3-CH3, 4-CH2, 5-CH, 6-CH2); 5.86 (1H, m, 2-CH). Mass spectrum,
m/z (Irel, %): 152 (9) [M]+, 109 (13), 82 (100), 77 (2.9), 67 (3.4), 54 (8.7), 43 (5.8), 39 (8.7).
Recyclization of 3,5-Diacetyl-1,2,6-trimethyl-4-phenyl-1,4-dihydropyridine (1f). Conc. HCl (8.0 ml,
84.8 mmol) was added to a solution of the 1,4-DHP (4.0 g, 14 mmol) in 80% ethanol (47 ml) and the mixture
refluxed for 8 h. The reaction mixture, after treatment analogous to that given above, was chromatographed
(hexane–TBME–MeOH, 10 : 2 : 1, Silasorb). Two fractions were collected. The first fraction, consisting
of cyclohexenone 2f and cyclohexadiene 4, was chromatographed once more (toluene–TBME, 5 : 1, Silasorb)
and ketone 2f (0.79 g: 30%) and hydroxy product 4 (0.07 g, 2%) were isolated. From the second fraction
cyclohexenone 3 (0.57 g: 18%) was isolated.
4-Acetyl-3-methyl-5-phenylcyclohex-2-enone (3). Mp 92-95°C. IR spectrum, ν, cm-1: 1661 (C=O),
1
1701 (C=O). H NMR spectrum (600 MHz, C6D6), δ, ppm (J, Hz): 1.36, (3H, s, 3-CH3); 1.44 (3H, s, COCH3);
2.30 (1H, dd, J = 11.8, J = 16.4, CH2); 2.51 (1H, dd, J = 4.4, J = 16.4, CH2); 3.10 (1H, d, J = 8.9, 4-CH);
3.19 (1H, m, 5-CH); 6.00 (1H, m, 2-CH); 6.85 (2H, dd, J = 1.4, J = 6.9, o-CH); 7.02 (1H, tt, J = 1.4, J = 7.3,
p-CH); 7.06 (2H, m, m-CH). 13C NMR spectrum (150 MHz, CDCl3), δ, ppm: 22.6 (3-CH3); 31.4 (COCH3);
42.6 (6-CH2); 44.0 (5-CH); 60.7 (4-CH); 127.2 (2', 6'-CH); 127.4 (4'-CH); 129.0 (3', 5'-CH); 129.1 (2-CH);
140.9 (1'-CH); 156.5 (3-C); 197.1 (1-C=O); 207.9 (COCH3). Found, %: C 78.66; H 7.08. C15H16O2.
Calculated, %: C 78.92; H 7.06.
1
1,5-Diacetyl-2-hydroxy-4-methyl-6-phenylcyclohexa-1,3-diene (4). H NMR spectrum (200 MHz,
CDCl3), δ, ppm (J, Hz): 1.86 (3H, d, J = 1.3, 4-CH3); 1.94 (3H, s, 5-COCH3); 2.27 (3H, s, 1-COCH3); 3.20 (1H,
d, J = 1.1, H-5); 4.27 (1H, d, J = 1.1, H-6); 6.19 (1H, m, H-3). 13C NMR spectrum (150 MHz, CDCl3), δ,
ppm: 22.5 (4-CH3); 24.5 (1-COCH3); 28.0 (5-COCH3); 41.8 (5-CH); 62.9 (6-CH); 104.2 (C-1); 125.2 (3-CH);
127.0 (4'-CH); 127.1 (2', 6'-CH); 128.8 (3', 5'-CH); 142.4 (C-1'); 149.2 (C-4); 180.4 (C-2); 191.0 (1-CO);
204.8 (5-CO). Mass spectrum, m/z (Irel, %): 270 (19) [M]+ (19), 252 (5) [M-18]+, 227 (65), 209 (16), 185 (27),
135 (9), 77 (10), 43 (100).
Recyclization of Dihydropyridines 1i-k in Hydrochloric Acid Solution. Recyclization of DHP 1j
in 1.0 M HCl and 1i in 1.8 M HCl was carried out as indicated above for 4 h. The reaction mixture was diluted
with water, extracted with CH2Cl2, the solvent distilled off, and the residue fractionated in vacuum. From
pyridine 1i (9.2 g: 34 mmol) ketone 2c (0.47 g: 31%) was obtained of bp 56-58°C (1.8 mbar). Further fraction
collected at 92-93°C (0.8 mbar) was a mixture of monoesters 8g, 9g, 11i, and 12i (3.0 g, yield 40%, ratio 2 : 1 :
10 : 2.5). From dihydropyridine 1j (11.3 g, 40 mmol) ketone 2d (0.80 g: 12%) was obtained of bp 60°C
(1.2 mbar). An intermediate fraction collected at 80-100°C (1.2 mbar) consisted of ketone 2d and a mixture of
monoesters 8h, 9h, 11j, and 12j (0.42 g). The fraction of bp 105-111 oC (1.2 mbar) was a mixture of monoesters
8h, 9h, 11j, and 12j (4.1 g, 41%, ratio 3 : 2 : 11 : 3). The pairs of diastereomers 8g,h, 9g,h, 11i,j, and 12i,j were
resolved chromatographically (hexane–TBME–MeOH, 125 : 25 : 1, Silasorb).
47

The reaction mixture obtained on recyclizing DHP 1k (1.0 g: 3.2 mmol) in 1.4 M HCl was resolved
chromatographically (hexane–TBME–MeOH, 5 : 2 : 1, Silasorb) after work up. Ketone 1f (0.17 g: 28%), pure
ester 11k (0.16 g: 21%), and a mixture of regioisomers 11k and 9k (0.05 g: 10%, ratio 1 : 1) were obtained.
Ethyl Esters of 4-Methyl-2-oxo-6-propylcyclohex-3-enecarboxylic Acids 12j and 11j. 13C NMR
spectrum (150 MHz, CDCl3), δ, ppm: isomer 12j, 13.8 ((CH2)2CH3); 14.0 (OCH2CH3); 19.6 (CH2CH2CH3);
24.3 (4-CH3); 34.5-36.7 (C-5, C-6, CH2CH2CH3); 55.6 (C-1); 60.70 (OCH2CH3); 125.0 (C-3); 161.8 (C-4);
168.3 (2-C=O); 194.2 (1-C=O); isomer 11j, 13.9 ((CH2)2CH3); 14.0 (OCH2CH3); 19.1 (CH2CH2CH3);
24.2 (4-CH3); 34.5-36.7 (C-5, C-6, CH2CH2CH3); 59.3 (C-1); 60.8 (OCH2CH3); 125.3 (C-3); 163.8 (C-4);
170.25 (C-2); 194.3 (COOEt).
Ethyl Ester of 2-Methyl-4-oxo-6-propylcyclohex-2-enecarboxylic Acid (8h). IR spectrum, ν, cm-1:
1674 (C=O), 1730 (C=O). 13C NMR spectrum (150 MHz, CDCl3), δ, ppm: 13.9 ((CH2)2CH3); 14.0 (OCH2CH3);
19.7 (CH2CH2CH3); 23.0 (2-CH3); 35.9 (CH2CH2CH3); 37.3 (C-5); 40.3 (C-6); 52.8 (C-1); 61.3 (OCH2CH3);
128.1 (C-3); 155.8 (C-2); 171.9 (4-C=O); 198.2 (1-C=O).
Ethyl Ester of 2-Methyl-4-oxo-6-phenylcyclohex-2-enecarboxylic Acid (9k). Mp 45.5-46.5°C.
1H NMR spectrum (200 MHz, C6D6), δ, ppm (J, Hz): 0.62 (3H, t, J = 1.4, OCH2CH3); 1.52 (3H, t, J = 1.3,
2-CH3); 2.23 (1H, dd, J = 16.4, J = 12.3, H-5); 2.53 (1H, dd, J = 16.4, J = 4.3, H-5); 3.15 (1H, d, J = 9.7, H-1);
3.43 (1H, m, H-6); 3.65 (2H, m, OCH2CH3); 5.93 (1H, m, H-3); 6.84-7.08 (5H, m, C6H5). Found, %: C 74.10;
H 7.04. C16H18O3. Calculated, %: C 74.40; H 7.02.
The ethyl ester of 4-methyl-2-oxo-6-phenylcyclohex-3-enecarboxylic acid (11k) corresponded in all
characteristics with the literature data of [15].
Recyclization of Dihydropyridines 1g,h under the Action of 0.6 M HCl. The requisite amount
of conc. HCl was added to a solution of 1,4-DHP 1g,h in 80% ethanol and the obtained mixture was refluxed for
10 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The solvent was evaporated, and
the residue, a yellow oil, was resolved chromatographically (hexane–TBME–MeOH, 10 : 4 : 1, Silica gel) into
fractions.
The first fraction, containing diesters 5-7, was chromatographed once again (toluene–TBME, 5 : 1,
Silasorb) and a mixture of the indicated esters was obtained. The second fraction was a mixture of monoesters 8,
9, and diester 10. The third fraction, consisting of diester 10 with contaminating monoesters 8 and 9, was
chromatographed again (toluene–TBME, 5, 1, Silasorb) and diester 10 was isolated as a pure product. The yield
and ratio of diesters, obtained on recyclization of both DHP 1g and 1h was the same – 34% and 5 : 6 : 7, 1 : 1 : 0.2.
The ratio of products isolated from the second fraction on recyclization of DHP 1g was 8g : 9g : 10g, 4 : 1 : 5, yield
was 26%. Yield of diester 10g was 6%.
As with the recyclization of DHP 1h the ratio of products in the second fraction 8h : 9h : 10h was
4 : 20 : 5, 22% yield. Yield of diester 10h from the third fraction was 8%.
Diethyl Esters of 2-Ethyl-4-methyl-6-oxocyclohex-4-ene-1,3-dicarboxylic Acids 5g and 7g.
13C NMR spectrum (100 MHz, C6D6), δ, ppm: isomer 5g, 7.0 (CH2CH3); 19.9 (4-CH3); 22.3 (CH2CH3);
38.5 (2-CH); 48.4 (3-CH); 54.7 (1-CH); 58.2-58.7 (1-OCH2CH3, 3-OCH2CH3); 125.5 (5-CH); 126.3-127.8
(1-OCH2CH3, 3-OCH2CH3); 153.8 (C-4); 167.5 (1-C=O); 169.2 (3-C=O); 190.4 (6-C=O); isomer 7g, 9.5 (CH2CH3);
19.8 (4-CH3); 22.8 (CH2CH3); 39.8 (2-CH); 49.5 (3-CH); 52.3 (1-CH); 58.2-58.7 (1-OCH2CH3, 3-OCH2CH3);
125.2 (5-CH); 126.3-127.8 (1-OCH2CH3, 3-OCH2CH3); 155.2 (C-4); 166.4 (1-C=O); 167.5 (3-C=O); 189.6 (6-
C=O).
Diethyl Ester of 2-Ethyl-6-hydroxy-4-methylcyclohexa-3,5-diene-1,3-dicarboxylic Acid (6g).
13C NMR spectrum (100 MHz, C6D6), δ, ppm: 9.2 (CH2CH3); 21.8 (4-CH3); 24.9 (CH2CH3); 47.4 (1-CH);
34.4 (2-CH); 58.2-58.7 (1-OCH2CH3, 3-OCH2CH3); 94.4 (3-CH); 119.2 (5-CH); 126.3-127.8 (1-OCH2CH3,
3-OCH2CH3); 142.9 (C-4); 164.7 (1-C=O); 169.2 (3-C=O); 170.7 (6-COH).
Recyclization of Dihydropyridine 1l under the Action of 6 M HCl. A solution of 1,4-dihydropyridine
1l (1.2 g: 4.2 mmol) and conc. HCl (22 ml) in ethanol (15 ml) was refluxed for 7.5 h. The reaction mixture was
diluted with water and extracted with CH2Cl2. The solvent was evaporated and the residue, a yellow oil, was
48

separated chromatographically (CH2Cl2–EtOAc, 30 : 1, Silica gel) into two fractions. The first fraction contained
cyclohexenecarbonitrile 13 and the second pyridine 14.
4-Methyl-2-oxo-6-phenylcyclohex-3-enecarbonitrile (13). Yield 0.17 g (20%). Mp 129-130°C.
1
IR spectrum, ν, cm-1: 2249 (C≡N), 1670 (C=O). H NMR spectrum (200 MHz, CDCl3), δ, ppm (J, Hz):
2.05 (3H, s, 4-CH3); 2.55-2.73 (2H, m, 4-CH2); 3.41-3.59 (1H, m, H-6); 3.74 (1H, d, J = 13.0, H-1); 6.08 (1H,
m, H-3); 7.24-7.47 (5H, m, C6H5). Found, %: C 79.60; H 6.42; N 6.35. C14H13NO. Calculated, %: C 79.59; H
6.20; N 6.63.
2,6-Dimethyl-4-phenylnicotinic Acid Nitrile (14) (23% yield) corresponded in all respects with
the literature data of [16].
Rate Constants (k) Determination of 1,4-DHP ring opening in Acidic Medium. Acid (1 ml),
prepared from conc. HCl and water so as to provide the required concentration of HCl in the reaction medium,
was added to a boiling solution (50 ml) of the 1,4-DHP (4.10-3 M) in 50% ethanol. The solution was boiled and
samples of 1.5 ml were taken directly after adding the acid and at intervals of 1, 2-5 min, or 5, 10, 15 min
depending on the rate of hydrolysis of the 1,4-DHP. Each sample was diluted with ethanol up to 25 ml and the
concentration of 1,4-DHP was determined by measuring the UV absorption at the maximum characteristic of
each 1,4-DHP.
The work was carried out with the financial support of the European Social Fund.
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