Interaction of 3-chloro-2-halopropenyl ketones with β-aminocrotonic acid ethyl ester

Article abstract of DOI:10.1007/s10593-005-0269-2

The reaction of 3-chloro-2-halo-1-propenyl ketones with β-aminocrotonic acid ethyl ester leads to the formation of ethyl esters of 6-alkyl(aryl, benzyl, cyclohexyl)-4-chloromethyl-2-methylnicotinic acids. It was established that at increased temperatures

Full text of DOI:10.1007/s10593-005-0269-2

Chemistry of Heterocyclic Compounds, Vol. 41, No. 8, 2005
INTERACTION OF 3-CHLORO-
2-HALOPROPENYL KETONES WITH
β-AMINOCROTONIC ACID ETHYL ESTER
R. A. Gadzhili, A. G. Aliev, R. A. Nadzhafova, and R. I. Ibragimov
The reaction of 3-chloro-2-halo-1-propenyl ketones with β-aminocrotonic acid ethyl ester leads to the
formation of ethyl esters of 6-alkyl(aryl, benzyl, cyclohexyl)-4-chloromethyl-2-methylnicotinic acids. It
was established that at increased temperatures the compounds obtained are partially converted into the
corresponding dihydrofuro[3,4-c]pyridines.
Keywords: 3-chloro-2-halo-1-propenyl ketones, dihydrofuro[3,4-c]pyridines, β-aminocrotonic acid
ethyl ester, 6-alkyl(aryl, benzyl, cyclohexyl)-4-chloromethyl-2-methylnicotinic acid ethyl esters.
The interaction of 2,3-dichloropropyl alkyl ketones with alkyl esters of aminoacetic acid leads to the
preparation of 1-alkoxycarbonylmethyl-2-alkylpyrroles [1], but in the case of the interaction of β-chlorovinyl
ketones with β-aminocrotonic acid ethyl ester it leads to nicotinic acid ethyl esters [2]. We have also established
that the interaction of 2,3-dichloropropenyl alkyl ketones with β-aminocrotonic acid ethyl ester leads to the
preparation of ethyl esters of 6-alkyl-4-chloromethyl-2-methylnicotinic acids [3].
However further investigations showed that during the vacuum distillation of the products of this
reaction, together with the ethyl esters of 6-alkyl-4-chloromethyl-2-methylnicotinic acids 2a-e, starting with
R ≥ C2H5, partial conversion of the latter into 6-alkyl-4-methyl-2-oxo-1,2-dihydrofuro[3,4-c]pyridines 3b-d
occurs. It was established that in a series of ethyl esters of 6-alkyl-4-chloromethyl-2-methylnicotinic acids the
yield of lactones 3 increases sharply with an increase in radical R. For example, on distilling nicotinic acid
derivatives 2a-e lactones 3b 8, 3c 15, 3d 24, and 3e 36% were formed as by-products. An explanation of this
might be the fact that depending on the increase in alkyl radical the boiling point of the compound being distilled
increases and with it the probability of thermal intramolecular cyclization of compounds 2a-e is increased. When
distilling the ethyl esters of 6-benzyl(phenyl, p-tolyl, p-chlorophenyl, cyclohexyl)-4-chloromethyl-2-
methylnicotinic acids 2f-j complete lactonization was observed (Scheme 1).
With the aim of preventing intramolecular cyclization of compounds 2f-j into lactones the appropriate 6-
benzyl(phenyl, p-tolyl, p-chlorophenyl, cyclohexyl)-derivatives of nicotinic acid were isolated and identified as
the hydrochlorides.
The reaction was carried out in ether or methanol in the presence of an equimolar quantity of
triethylamine at 35-40°C for 5 h and the ethyl esters of 6-alkyl(aryl, benzyl, cyclohexyl)-4-chloromethyl-2-
methylnicotinic acids 2a-j or their hydrochlorides were obtained in 57-84% yield.
On distilling the nicotinic acid derivatives 2a-e at a residual pressure of 20-30 mm Hg they were
completely converted into the corresponding lactones 3a-e.
__________________________________________________________________________________________
Institute of Polymer Materials, Azerbaijan National Academy of Sciences, Sumgait, Az5004; e-mail:
ipoma@dcacs.ab.az. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1184-1188, August,
2005. Original article submitted December 2, 2003.
0009-3122/05/4108-1009©2005 Springer Science+Business Media, Inc.
1009

Scheme 1
CH2Cl
CO2Et
Me
CH2Cl
Hal
N
R
2a–j
CO2Et
HC
+
O
R
H2N
Me
R
O
O
1a–j
N
Me
3a–j
1-3 a R = Me, b R = Et, c R = Pr, d R = Bu, e R = C5H11, f R = Bn, g R = Ph,
h R = m-C6H4Me, i R = m-C6H4Cl, j R = c-C6H11; 1a-j Hal = Cl, Br
The formation of lactones 3 is a successful confirmation of the structure of the nicotinic acid ethyl esters
2. This is very important since, in principle, it is possible that the other regiodirected cyclocondensation of halo
ketones 1 with the ethyl ester of β-aminocrotonic ester may occur, bringing about, as a result of the initial
nucleophilic substitution of the amino group by the halogen atom in position 2 of ketones 1, the formation of the
isomeric ethyl esters of 4-alkyl(aryl, benzyl, cyclohexyl)-6-chloromethyl-2-methylnicotinic acids, which are not
capable of intramolecular cyclization.
It may therefore be asserted that the reaction between 2,3-dihalo ketones 1 and the ethyl ester of
β-aminocrotonic acid begins with the formation of a Schiff's base with its subsequent intramolecular cyclization
with the elimination of a molecule of hydrogen halide and conversion into the ethyl ester of nicotinic acid 2
(Table 1).
Characteristic absorption bands were observed in the IR spectra of compounds 2 and 3 for the pyridine
ring at 2995-3400 (γ=C–H), 1510-1595 (γC=C), 1120-1200 (δ=C–H), 1716-1730 (γC=O), 1235-1282 (γC–O–C),
1755-1780 (γC=O lactone), and 710-745 cm-1 (γC–Cl), the positions of which are in agreement with the data of [4].
Characteristic singlet signals were present in the 1H NMR spectra of compounds 2 and 3 for the protons
of the pyridine ring, and of the CH2 and CH3 groups (Table 2). There were triplet and quadruplet signals for the
protons of the CO2CH2CH3 group and also signals for the protons of the R groups.
The described method enables the synthesis of the previously unknown ethyl esters of
4-chloromethylnicotinic acids selectively and in high yield. The products are possible starting materials for
obtaining structural analogs of vitamin PP, cardiamine, etc.
EXPERIMENTAL
The IR spectra were obtained on UR-20 and Specord M-80 spectrometers using a thin film for liquid
1
compounds and nujol for crystalline substances. The H NMR spectra were recorded on a Tesla BS-487B
(80 MHz), internal standard was HMDS (δ 0.05 ppm) for 5-10% solutions of substances in CCl4 or acetone-d6.
The purity of the synthesized compounds was checked by TLC on Silufol UV-254 plates.
The initial 2,3-dichloropropenyl ketones were obtained by the procedure of [5].
1010

TABLE 1. Characteristics of Compounds 2 and 3
Found, %
——————
Calculated, %
Com-
pound*
Empirical
formula
Yield,
%
Т, °С*2
С
Н
N
2a
2b
2c
2d
2e
2f
C11H14СlNO2
C12H16СlNO2
C13H18СlNO2
C14H20СlNO2
C15H22СlNO2
C17H18СlNO2·HСl
C16H16СlNO2·HСl
C17H18СlNO2·HСl
C16H15Сl2NO2·HСl
C16H22СlNO2·HСl
C9H9NO2
58.59
58.02
59.96
59.62
61.42
61.06
62.73
62.34
64.01
63.49
60.55
60.00
59.46
58.88
60.39
60.00
53.47
53.93
57.19
57.83
66.85
66.26
68.23
67.80
68.67
69.11
69.59
70.24
71.84
71.23
75.91
75.31
6.37
6.15
6.81
6.62
7.29
7.05
7.58
7.42
7.63
7.76
5.67
5.59
5.33
5.21
5.72
5.59
4.63
4.87
6.71
6.93
5.49
5.52
6.47
6.21
6.98
6.81
7.11
7.32
7.93
7.76
5.67
5.44
6.42
6.15
6.14
5.80
5.31
5.48
5.02
5.19
4.86
4.94
4.45
4.12
4.50
4.29
4.37
4.12
3.88
3.75
4.37
4.22
9.18
8.59
7.69
7.91
7.86
7.33
6.43
6.86
6.39
6.28
6.01
5.86
121-123 (2)
128-130 (2)
134-136 (1)
148-149 (2)
156-158 (2)
124-125
137-139
132-133
157-158
190-192
109-110
85-86
84
76
71
64
57
75
80
72
65
68
75
77
73
67
69
72
71
73
68
70
2g
2h
2i
2j
3a
3b
3c
3d
3e
3f
C10H11NO2
C11H13NO2
72-74
C12H15NO2
65-66
C13H17NO2
59-60
C15H13NO2
54-56
3g
3h
3i
C14H11NO2
74.20
74.67
75.77
75.31
64.42
64.74
72.18
72.72
4.58
4.90
5.32
5.44
3.68
3.85
7.09
7.36
6.47
6.22
5.73
5.86
5.67
5.39
6.17
6.06
50-51
C15H13NO2
47-48
C14H10ClNO2
C14H17NO2
61-63
3j
87-89
_______
20
20
* 2 а nD = 1.5207, d420 = 1.1558; b nD = 1.5175, d420 = 1.1339;
c nD20 = 1.5140, d420 = 1.1123; d nD20 = 1.5108, d420 = 1.0014, e nD20 = 1.5075,
d420 = 0.9918; f-j – hydrochlorides.
*2 For compounds 2a-e bp (mm Hg) are given, for compounds 2f-j and 3a-j
mp are given.
TABLE 2. 1H NMR Spectra of Compounds 2 and 3
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
CH2–CH3, q, t
=CH, s
CH2, s
CH3, s
R
2а
2h
2i
6.90
6.84
7.06
7.00
7.02
7.04
4.49
4.45
4.59
5.01
5.05
5.03
2.46
2.53
2.58
2.72
2.70
2.73
4.26, 1.30 (J = 6.9)
4.18, 1.27 (J = 6.8)
2.43, s
3.20, s; 7.32-8.00, m
7.16-7.65, m
4.33, 1.35 (J = 7.0)
3a
3b
3i
—
—
—
2.45, s
1.23, t ; 2.87, q (J = 7.0)
7.30-7.88, m
1011

Ethyl Esters of 6-Alkyl-4-chloromethyl-2-methylnicotinic Acids 2a-e. Ethyl β-aminocrotonate
(12.9 g, 0.1 mol) and triethylamine (14 ml, 0.1 mol) were added dropwise to a solution of 2-bromo-3-chloro- or
2,3-dichloropropenyl alkyl ketones 1a-e (0.1 mol) in ether (100 ml) at 20-25°C, and the reaction mixture was
boiled for 5 h. After cooling, it was washed with water, the aqueous layer was extracted with ether, the ether
extracts were combined, and dried over MgSO4. After distilling off the solvent the residue was fractionated in
vacuum.
Ethyl Ester Hydrochlorides of 6-Benzyl(phenyl, p-tolyl, p-chlorophenyl, cyclohexyl)-4-
chloromethyl-6-methylnicotinic Acids 2a-j. Analogously to the indicated method, an anhydrous ether solution
of the ethyl esters of nicotinic acid 2a-j was obtained from 2,3-dichloropropenyl benzyl(phenyl, p-tolyl,
p-chlorophenyl, cyclohexyl) ketones 1a-j (0.1 mol), ethyl β-aminocrotonate (12.9 g, 0.1 mol), and triethylamine
(14 ml, 0.1 mol), after appropriate processing. A stream of dry hydrogen chloride was passed through this
solution, the precipitated crystals were filtered off, and recrystallized from ethyl alcohol.
6-Alkyl(benzyl, phenyl, p-tolyl, p-chlorophenyl, cyclohexyl)-4-methyl-3-oxo-dihydrofuro[3,4-c]-
pyridines 3a-j. The ether solution of ethyl esters of nicotinic acid 2a-j was evaporated in vacuum and subjected
to vacuum distillation at a residual pressure of 20-30 mm Hg. After recrystallization from hexane the
dihydrofuro[3,4-c]pyridines were obtained.
REFERENCES
1.
R. A. Gadzhili, R. A. Nadzhafova, V. G. Dzhafarov, S. S. Asadova, and V. M. Fedoseev, Khim.
Geterotsikl. Soedin., 769 (1993).
2.
3.
N. K. Kochetkov, A. Gonsales, and A. N. Nesmeyanov, Dokl. Akad. Nauk SSSR, 59, 609 (1951).
I. I. Ibragimov, A. N. Kost, A. G. Aliev, S. P. Godzhaev, R. A. Gadzhily, and L. A. Sviridova, Authors
Certificate SSSR 515746; Byull. Izobret., No. 20, 65 (1976).
4.
5.
A. J. Gordon and R. A. Ford, Chemists' Companion. Handbook of Practical Data, Techniques, and
References, Wiley-Interscience, New York (1972), 560 pp; in Russian version pp. 206 and 219.
I. I. Ibragimov, E. I. Mamedov, A. G. Aliev, T. S. Mekhtieva, Sh. Z. Mekhtieva, S. A. Guseinov, and
T. I. Abdullaeva, Zh. Org. Khim., 26, 1654 (1990).
1012