Synthesis of 1-aryl-4-azolylbutanones

Article abstract of DOI:10.1007/s10593-005-0265-6

A convenient method was developed for the synthesis of substituted 4-azolyl-1-arylbutanones from the available γ-chlorobutyrophenones by successive stages of transformation into ketals, alkylation of sodium imidazolate or 1,2,4-triazolate by the ketals in

Full text of DOI:10.1007/s10593-005-0265-6

Chemistry of Heterocyclic Compounds, Vol. 41, No. 8, 2005
SYNTHESIS OF 1-ARYL-
4-AZOLYLBUTANONES
D. A. Karachev and S. V. Popkov
A convenient method was developed for the synthesis of substituted 4-azolyl-1-arylbutanones from the
available γ-chlorobutyrophenones by successive stages of transformation into ketals, alkylation of
sodium imidazolate or 1,2,4-triazolate by the ketals in DMF, and removal of the ketal protection.
Keywords: 1-aryl-4-azolyl-1-butanones, dioxolanes, p-substituted γ-chlorobutyrophenones, imidazole,
ketals, 1,2,4-triazole, alkylation of azoles.
Many imidazole and 1,2,4-triazole derivatives of aliphatic-aromatic ketones have fungicidal
(antimycotic) activity [1, 2]. Most of them are derivatives of alkanophenones, in which the azolyl group is at the
α-position to the carbonyl group, e.g., such fungicides as etaconazole and antimycotic agents fluconazole and
ketoconazole [3]. At the same time substituted butyrophenones and isobutyrophenones with nitrogen-containing
heterocycles at the ω-position, used as neuroleptics (haloperidol, droperidol) and antispasmodic preparations
(midocalm), are known [4]. Unknown ω-azolylalkanophenones and their derivatives are therefore of interest as
subjects for investigation of biological activity.
Descriptions of the alkylation of azoles by various halo-substituted compounds are quite often found in
the literature [5-7]. There are also examples of the alkylation of saturated nitrogen-containing heterocycles by
substituted γ-chlorobutyrophenones: Substituted piperazines [8], compounds of the tropine series [9], and most
often substituted piperidines [10]. However, data on 4-azolylbutyrophenones and their analogs are extremely
limited. The production of γ-imidazolylpropyl 3-fluorenyl ketone by opening 3-fluorenyl cyclopropyl ketone
was mentioned [11]. A single example* of the production of γ-imidazolylbutyrophenone with a yield of 50% by
the reaction of 4-bromo-γ-chlorobutyrophenone with an excess of imidazole in DMF is known [12]. Prolonged
heating of the reaction mass (48 h) at 95-100°C leads to the formation of a mixture of alkylation products, from
which the required product can be isolated by column chromatography. In addition, as shown by our
investigations, triazole derivatives cannot be obtained by this method. In the present work we describe a
convenient method for the production of substituted γ-azolylbutyrophenones.
Whereas the alkylation of 4-hydroxy-4-phenylpiperidine with γ-chlorobutyrophenone leads to
γ-(4-hydroxy-4-phenylpiperidin-1-yl)butyrophenone with a yield of 70% [10], the direct alkylation of azoles
with the corresponding γ-chlorobutyrophenones by the analogous method did not give satisfactory results.
____________
* The search was made at the Moscow STN information center of the N. D. Zelinsky Institute of Organic
Chemistry, Russian Academy of Sciences, with a grant from the Russian Fundamental Research Fund
No. 00-03-40142 and the Collective Use Center.
__________________________________________________________________________________________
D. I. Mendeleev University of Chemical Technology of Russia, Moscow; e-mail: popkovsv@rctu.ru.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1161-1167, August, 2005. Original article
submitted December 30, 2003.
0009-3122/05/4108-0987©2005 Springer Science+Business Media, Inc.
987

The prototype of the procedure for the reaction of γ-chlorobutyrophenone with imidazole was the
method for the production of ε-dimethylaminocaprophenone [13]. A mixture of the chloro ketone with a fourfold
excess of imidazole in methanol was heated at 120°C for 24 h. The alkylation product was isolated through the
hydrochloride with subsequent purification by column chromatography (eluant 9:1 chloroform–2-propanol). As
a result it was possible to obtain the required γ-imidazolylbutyrophenone, but the yield amounted to only 10%.
It was possible to obtain γ-triazolylbutyrophenone by a method similar to the production of triadimefon
[14]. γ-Chlorobutyrophenone was boiled with a fourfold excess of triazole in acetonitrile for 50 h. Potassium
iodide was used as catalyst. After isolation by column chromatography (eluant 9:1 chloroform–2-propanol)
γ-(1,2,4-triazol-1-yl)butyrophenone was obtained with a yield of 12%.
The low yields are probably due to the occurrence of side reactions involving the carbonyl group under
the proposed conditions (basic medium, elevated temperature) together with the insufficient activity of the
chlorine at the γ-position to the carbonyl group. In addition, the low alkylating ability of the
γ-chlorobutyrophenone may be due to the formation of the intermediate stable phenyltetrahydrofuran
carbocation first proposed in [15].
+
CH2
+
O
O
+
O
O
C
+
C
We therefore chose a scheme of transformations with prior protection of the carbonyl group for the
production of the required compounds, and this made it possible to realize the alkylation of the azole under fairly
"rigorous" conditions. For this purpose we chose the method for the production of ketals widely used in
laboratory practise and described in detail in the literature [16, 17]. The diethyl ketals 2a-d were synthesized
with yields of 77-87% by the reaction of the corresponding ketones 1a-d with alcohol. The ethylene ketals
(dioxolanes) 3a,d were obtained with yields of 64 and 94% by the reaction of the ketones 1a,d with ethylene
glycol (Table 1).
R
R
EtOH, HC(OEt)3
O
O
O
+
Cl
H , ∆
Cl
X
HOCH2CH2OH
X
TsOH, C6H6, ∆
2a–d, 3a,d
1a–d
1-3 a X = H, d X = Br; 1, 2 b X = F, c X = Cl; 2a-d R = Et, 3a,d 2R = CH2CH2
The obtained ketals were used to alkylate sodium azolates in DMF. Here the reaction with the triazolate
4b was conducted at a higher temperature and for a longer time than with the imidazolate 4a, since the product
from 4-substitution of the triazole was converted by prolonged heating into the main thermodynamically stable
product from 1-substitution of 1,2,4-triazole [18]. For purification from the nonpolar impurities the obtained
ketals 5-8 were isolated in the form of hydrochlorides, and here during extraction with hydrochloric acid the
diethyl ketals 5a-d and 6a-d were hydrolyzed to the corresponding γ-azolylbutyrophenones 9a-d and 10a-d. The
dioxolanes 7d and 8a,d proved considerably more stable, and their hydrolysis therefore required boiling in a
water–alcohol solution of hydrochloric acid for several hours. At the stage of isolation of the free bases the yield
988

TABLE 1. The Characteristics of Compounds 2a-d, 3a,d, 9a-d, and 10a-d
Found, %
Calculated, %
bp, °С
(mm Hg),
mp, °С
——————
Com-
pound
Empirical
formula
Yield,
%
C
H
N
Hal*
C14H21ClO2
—
—
—
—
13.57
13.81
12.74
12.90
103-105 (0.2)*2
84
77
2a
2b
C14H20ClFO2
95-97
(0.06)
118-120 (0.2)*2
C14H20Cl2O2
—
—
—
—
12.05
12.18
10.29
10.56
78
87
2c
C14H20BrClO2
138-140
(0.2)
2d
C12H15ClO2
63.50
63.58
6.83
6.70
15.52
15.64
97-100
(0.18),
47-48
64
3a
C12H14BrClO2
C13H14N2O
46.93
47.16
4.75
4.62
37.58
37.75
138-143
(0.2)
94
80
3d
9a
72.53
72.87
6.83
6.59
12.91
13.07
77-79
167-170*3
C13H14ClFN2O
C13H14Cl2N2O
C13H13BrN2O
58.05
58.11
54.78
54.75
53.33
53.26
5.39
5.25
5.20
4.95
4.55
4.47
10.39
10.43
9.95
9.82
9.54
9.56
132-134*3
62*3
77*3
9b
9c
9d
24.62
24.86
27.03
27.26
163-165*3
84-86
44
167-169*3
61*4
C12H13N3O
67.19
66.96
6.17
6.09
19.66
19.52
80–82
70
10a
49*4
C12H13ClFN3O
C12H12ClN3O
53.53
53.44
50.20
50.37
5.08
4.86
4.66
4.58
15.63
15.58
14.75
14.68
120-122*3
78*3
10b
10c
24.49
24.78
63-64
63
122-124*3
C12H12BrN3O
49.23
49.00
4.38
4.11
14.35
14.35
26.88
27.16
87-89
64
10d
148-150*3
60*4
_______
* For compounds 2a-d the content of mineralized Cl after boiling with
EtONa is given.
*2 nD20 1.4947 (2a), 1.5106 (2c).
*3 In the form of the hydrochloride.
*4 The yield during production through the dioxolanes 3a,d.
was almost quantitative (90-95%). Most of the compounds were isolated with yields of 44-80% and were
characterized in the form both of the free γ-azolylbutyrophenones 9a,c,d and 10a,c,d and of the respective
hydrochlorides, while the fluorine derivatives 9b and 10b, which were low-melting substances, were
characterized only in the form of the hydrochlorides (Scheme 1).
During the formation of the ketals from the chlorobutyrophenones 1a-d the signals for the protons of the
chloromethylene groups in the 1H NMR spectra of compounds 2a-d and 3a,d (Table 2) are shifted upfield from
3.7 to 3.4 ppm. If the chlorine is replaced by an azole ring, on the other hand, there is a downfield shift of 0.9
ppm in the signal for the γ-methylene group, which is observed at ~4.4 ppm in both the imidazole and triazole
derivatives. Mass-spectrometric investigations of the substituted azolylbutyrophenones 9a,b and 10b made it
possible to conclude that the main direction of fragmentation under electron impact is accompanied by the
elimination of vinylazoles, as shown by the fragment ion with m/z 95 or 96 for the derivatives of imidazole and
1,2,4-triazole respectively, which has maximum intensity in the mass spectra of the investigated alkylazoles.
989

Scheme 1
R
R
N
O
O
N
N
_
Z
+
N
Na
2a–d, 3a,d
+
Z
DMF, ∆
X
4a,b
5a–d, 6a–d, 7d, 8a,d
N
1) HCl–H2O
2) Na2CO3
O
5a–d, 6a–d
7d, 8d
N
Z
X
9a–d, 10a–d
1) HCl–H2O–MeOH, ∆
2) Na2CO3
4 a Z = CH, b Z = N;
5, 6, 8–10 a X = H, 5, 6, 9, 10 b X = F, c X = Cl, 5–10 d X = Br;
5a–d, 6a–d R = Et; 7d, 8a,d 2R = CH2CH2; 5a–d, 7d, 9a–d Z = CH;
6a–d, 8a,d, 10a–d Z = N
TABLE 2. The Spectral Characteristics of Compounds 2a-d, 3a,d, 9a-d, and
10a-d
IR spectrum,
Com-
pound*
1Н NMR spectrum, δ, ppm (J, Hz)*2
ν, cm-1
1
2
3
1045, 1070, 1095 1.22 (6Н, t, J = 7.0, 2СН3); 1.43-1.50 (2Н, m, СН2СН2СН2);
2a
(C–O–C–O–C)
2.03-2.11 (2Н, m, СН2СН2СН2Cl); 3.34-3.44 (6Н, m, СН2Cl,
2ОСН2); 7.33 (3Н, t, J = 8.0, C6H5); 7.51 (2Н, d, J = 7.0, C6H5)
1012, 1045,
1065, 1095
(C–O–C–O–C)
1.21 (6Н, t, J = 7.1, 2СН3); 1.39-1.53 (2Н, m, СН2СН2СН2);
2.00-2.11 (2Н, m, СН2СН2СН2Cl); 3.30-3.48 (6Н, m, СН2Cl,
2ОСН2); 7.03 (2Н, d, J = 8.4, FC6H4); 7.46 (2Н, dd, 3J = 8.8, 4
J = 5.5, FC6H4)
2b
2c
2d
3a
1015, 1045,
1055, 1080
(C–O–C–O–C)
1.21 (6Н, t, J = 7.0, 2СН3); 1.40-1.51 (2Н, m, СН2СН2СН2);
2.01-2.12 (2Н, m, СН2СН2СН2Cl); 3.30-3.51 (6Н, m,
СН2СН2СН2Cl, 2ОСН2); 7.33 (2Н, m, J = 8.4, ClC6H4);
7.45 (2Н, m, J = 8.4, ClC6H4)
1010, 1055,
1070, 1090
(C–O–C–O–C)
1.22 (6Н, m, J = 7.0, 2СН3); 1.38-1.52 (2Н, m, СН2СН2СН2);
1.99-2.10 (2Н, m, СН2СН2СН2Cl); 3.28-3.48 (6Н, m,
СН2СН2СН2Cl, 2ОСН2); 7.37 (2Н, d, J = 8.6, BrC6H4);
7.49 (2Н, d, J = 8.6, BrC6H4)
1010, 1030,
1040, 1095
1.83-1.93 (2Н, m, СН2СН2СН2Cl); 2.02-2.09 (2Н, m,
СН2СН2СН2Cl); 3.55 (2Н, t, J = 6.0, СН2Cl); 3.77 (2Н, t,
(C–O–C–O–C)
J = 6.0, ОСН2СН2О); 4.05 (2Н, t, J = 6.0, ОСН2СН2О);
7.25-7.38 (3Н, m, C6H5); 7.46 (2Н, d, J = 6.0, C6H5)
1008, 1040,
1070, 1100
(C–O–C–O–C)
1.75-1.93 (2Н, m, СН2СН2СН2Cl); 1.93-2.08 (2Н, m,
СН2СН2СН2Cl); 3.54 (2Н, t, J = 6.3, СН2Cl); 3.76 (2Н, t, J = 6.9,
ОСН2СН2О); 4.03 (2Н, t, J = 7.0, ОСН2СН2О,); 7.33 (2Н, J = 8.4,
BrC6H4); 7.48 (2Н, J = 8.4, BrC6H4)
3d
1660 (С=О),
1575 (C=N)
2.12 (2Н, q, J = 6.5, СН2СН2СН2); 3.15 (2Н, t, J = 6.9,
СН2СН2CO); 4.31 (2Н, t, J = 6.3, СН2СН2N); 6.95 (1Н, s, СН Im);
7.09 (1Н, s, СН Im); 7.40-7.56 (3Н, m, C6H5); 7.59 (1Н, s, СН Im);
7.99 (2Н, d, J = 7.5, C6H5)
9а
990

TABLE 2 (continued)
1
2
3
1670 (С=О),
1580 (C=N)
2.17 (2Н, q, J = 7.0, СН2СН2СН2); 3.11 (2Н, t, J = 7.1,
СН2СН2CO); 4.28 (2Н, t, J = 7.0, СН2СН2N); 7.36 (2Н, t. d,
3J = 8.8, 4J = 2.0, FC6H4); 7.69 (1Н, t, 3J = 1.7, СН Im); 7.84 (1Н, t,
3J = 1.7, СН Im); 8.05 (2Н, dd, 3J = 8.9, 4J = 5.6, 4J = 2.1, FC6H4);
9.25 (1Н, s, СН Im)
9b
1675 (С=О),
1575 (C=N)
2.15 (2Н, q, J = 7.0, СН2СН2СН2); 3.11 (2Н, t, J = 7.0,
СН2СН2CO); 4.29 (2Н, t, J = 6.9, СН2СН2N); 7.57 (2Н, d, J = 8.5,
ClC6H4); 7.69 (1Н, s, СН Im); 7.86 (1Н, s, СН Im);
7.98 (2Н, d, J = 8.5, ClC6H4); 9.28 (1Н, s, СН Im)
9c
1670 (С=О),
1570 (C=N)
2.23 (2Н, q, J = 7.0, СН2СН2СН2); 2.90 (2Н, t, J = 6.8,
СН2СН2CO); 4.34 (2Н, t, J = 6.9, СН2СН2N); 6.94 (1Н, s, СН Im);
7.08 (1Н, s, СН Im); 7.53 (1Н, s, СН Im); 7.59 (2Н, d, J = 8.5,
BrC6H4); 7.76 (2Н, d, J = 8.5, BrC6H4)
9d
1660 (С=О),
1580 (C=N)
2.35 (2Н, q, J = 6.6, СН2СН2СН2); 3.00 (2Н, t, J = 6.5,
СН2СН2CO); 4.32 (2Н, t, J = 6.5, СН2СН2N); 7.43-7.59 (3Н, m,
C6H5); 7.92 (2Н, d, J = 7.5, C6H5); 7.95 (1Н, s, СН triaz.);
8.07 (1Н, s, СН triaz.)
10а
10b
10c
10d
1670 (С=О),
1585 (C=N)
2.15 (2Н, q, J = 7.0, СН2СН2СН2); 3.09 (2Н, t, J = 7.0,
СН2СН2CO); 4.32 (2Н, t, J = 7.0, СН2СН2N); 7.35 (2Н, t, 3J = 8.7,
FC6H4); 8.02 (2Н, dd, 3J = 8.4, 4J = 5.6, FC6H4);
8.45 (1Н, s, СН triaz.); 9.21 (1Н, s, СН triaz.)
1660 (С=О),
1575 (C=N)
2.34 (2Н, q, J = 6.8, СН2СН2СН2,); 2.97 (2Н, t, J = 6.5,
СН2СН2CO); 4.22 (2Н, t, J = 6.6, СН2СН2N); 7.44 (2Н, d, J = 8.4,
ClC6H4); 7.89 (2Н, d, J = 8.4, ClC6H4); 7.95 (1Н, s, СН triaz.);
8.08 (1Н, s, СН triaz.)
1670 (С=О),
1578 (C=N)
2.34 (2Н, t, J = 6.7, СН2СН2СН2); 2.97 (2Н, t, J = 6.7,
СН2СН2CO); 4.33 (2Н, t, J = 6.7, СН2СН2N); 7.61 (2Н, d, J = 8.5,
BrC6H4); 7.77 (2Н, d, J = 8.5, BrC6H4); 7.95 (1Н, s, СН triaz.);
8.08 (1Н, s, СН triaz.)
_______
* Mass spectrum, m/z (I, %), 9a: 214 [М]+ (24), 147 (11), 120 (39), 105 (75),
95 (100); 9b: 232 [М–36]+ (34), 165 (11), 138 (42), 123 (74), 95 (100); 10b:
233 [М–36]+ (1), 164 (17), 138 (21), 123 (100), 96 (78); compounds 9b,c
and 10b in the form of the hydrochloride.
*2 Im = imidazole, triaz. = triazole.
EXPERIMENTAL
The IR spectra were recorded on a Specord M-80 instrument in thin films (liquids) and in Vaseline oil
1
(solids). The H NMR spectra were obtained on Bruker AC-200 (200 MHz) and Bruker AM-300 (300 MHz)
spectrometers with deuterochloroform as solvent and in DMSO-d6 for the hydrochlorides of azolyl ketones 9b,c
and 10b. The mass spectra were obtained on a Kratos MS-30 instrument (Great Britain) with 70-eV electrons.
The reactions and the purity of the obtained compounds were monitored by TLC on Silufol UV-254 plates in the
10:1 chloroform–ethanol system (development in UV light, treatment with
a
solution of
2,4-dinitrophenylhydrazine and the azoles with modified Dragendorf reagent [19]). The melting points were
determined on a Boetius bench.
The initial 1-aryl-4-chloro-1-butanones 1a-d were obtained by the acylation of substituted benzenes with
4-chlorobutyryl chloride by the Friedel–Crafts reaction [10].
Ketals of γ-Chlorobutyrophenones 2a-d and 3a,d. A. To a solution of the ketone 1a-d (32 mmol) and
triethyl orthoformate (96 mmol) in absolute ethanol (19 ml) we added conc. hydrochloric acid (1 ml). The
reaction mixture was stirred for 24 h, the acid was neutralized with triethylamine (12 mmol), the low-boiling
991

components were evaporated, the residue was distilled under the vacuum of an oil pump, and 1-aryl-4-chloro-
1,1-diethoxybutanes 2a-d were obtained.
B. A solution of the ketone 1a-d (87 mmol), ethylene glycol (131 mmol), and p-toluenesulfonic acid
(4.4 mmol) in dry benzene (100 ml) was boiled with a Dean–Stark tube until the release of water had stopped.
After cooling the reaction mass was washed with sodium carbonate solution (3 × 30 ml) and with water, and
dried with magnesium sulfate. The solvent was evaporated, the residue was distilled under the vacuum of an oil
pump, and the 2-aryl-1-(3-chloropropyl)-1,3-dioxolanes 3a,d were obtained.
Alkylation of Imidazole (General Procedure). We dissolved metallic sodium (100 mmol) in absolute
ethanol (40 ml) and added imidazole (100 mmol). The mixture was stirred, the ethanol was evaporated to
dryness under vacuum under the vacuum of a water-jet pump, and the sodium imidazolate 4a was obtained. We
dissolved the azolate 4a (100 mmol) by heating and stirring in DMF (90 ml) and added dropwise a solution of
the ketal 2a-d or 3a,d (83 mmol) in DMF (10 ml) over 30 min at 70°C. The reaction mass was stirred at the same
temperature for 24 h. The course of the reaction was monitored by TLC. After cooling the reaction mass was
filtered, the solvent was evaporated under vacuum, and the residue was dissolved in 100 ml of benzene and
washed with aqueous sodium carbonate solution (30 ml). The organic phase was extracted with 10%
hydrochloric acid solution (5 × 40 ml), and the extract was evaporated. The residue was recrystallized from
absolute 2-propanol, and 2-(4-bromophenyl)-2-[3-(1-imidazolyl)propyl]-1,3-dioxolane 7d (from the initial ketal
3d) or the hydrochlorides of the 1-aryl-4-(1-imidazolyl)-1-butanones 9a-d were obtained.
Alkylation of 1,2,4-Triazole (General Procedure). The reaction was carried out by a similar procedure
to the alkylation of imidazole with the exception that after the addition of the solution of the ketals 2a-d and 3a,d
to the solution of sodium triazolate 4b the reaction mixture was stirred at 110-120°C for 30-40 h. The
hydrochlorides of 2-aryl-2-[3-(1,2,4-triazol-1-yl)propyl]-1,3-dioxolanes 8a,d (from the initial ketals 3a,d) or the
hydrochlorides of 1-aryl-4-(1,2,4-triazol-1-yl)-1-butanones 10a-d were obtained.
Hydrolysis of Dioxolanes of γ-Azolylbutyrophenones 7d and 8a,d. A solution of the hydrochloride of
the dioxolane 7d or 8a,d (20 mmol) in a mixture of methanol (75 ml) and 2 N hydrochloric acid (75 ml) was
boiled for 3-4 h. The solvents were evaporated, the residue was recrystallized from absolute 2-propanol, and the
hydrochlorides of the azolyl ketones 9d or 10a,d were obtained.
The Free Bases of γ-Azolylbutyrophenones 9a-d and 10a-d. The hydrochlorides of the azolyl ketones
9a-d or 10a-d were dissolved in water, sodium carbonate solution was added to a basic reaction, and the product
was extracted with toluene. The extract was dried with magnesium sulfate, the solvent was evaporated under
vacuum, the residue was recrystallized from diisopropyl ether, and the γ-azolylbutyrophenones 9a-d or 10a-d
were obtained.
REFERENCES
1.
N. N. Mel'nikov, Pesticides. Chemistry, Technology, and Application [in Russian], Khimiya, Moscow
(1987), 712 pp.
2.
3.
L. V. Moshkova (editor), Medicines that You Choose [Russian translation], Mir, Moscow (2000), p. 607.
Yu. F. Krylov (editor), Register of Drugs of Russia. Encyclopedia of Drugs [in Russian], RLS-2000,
Moscow (2000), pp. 423, 987.
4.
5.
6.
7.
M. D. Mashkovskii, Drugs [in Russian], Vol. 2, Novaya Volna, Moscow (2000), pp. 67, 49.
M. Begtrup and P. Larsen, Acta Chem. Scand., 44, 1050 (1990).
E. F. Godefroi, J. Heeres, J. van Cutsem, and P. A. J. Janssen, J. Med. Chem., 12, 784 (1969).
K. Iizuka, K. Akahane, D. Momose, M. Nakazawa, T. Tanauchi, M. Kauvamura, I. Okyama, I. Kajiwara,
Y. Iguchi, T. Okada, K. Taniguchi, T. Miyamoto, and M. Hayashi, J. Med. Chem., 24, 1139 (1981).
P. A. J. Janssen, US Pat. 2997472; Chem. Abstr., 56, 11603 (1962).
8.
992

9.
J. P. Li and J. H. Biel, J. Med. Chem., 9, 917 (1969).
10.
P. A. J. Janssen, C. Van de Westeringh, A. H. M. Jageneau, P. J. A. Demoen, B. K. F. Hermans,
G. H. P. Van Daele, K. H. L. Schellekens, C. A. M. Van der Eycken, and C. J. E. Niemegeers, J. Med.
Pharm. Chem., 1, 281 (1959).
11.
W. Robertson, J. H. Krushinski, E. E. Beedle, J. D. Leander, D. T. Wong, and R. C. Rathbun, J. Med.
Chem., 29, 1577 (1986).
12.
13.
S. Upadhyaya and L. Bauer, J. Heterocycl. Chem., 29, 1053 (1992).
E. Ya. Borisova, I. A. Rubtsov, L. A. Botova, A. S. Lukashov, and E. M. Cherkasova, Izv. Vuzov.
Khimiya i Khim. Tekhnologiya, 366 (1977).
14.
15.
16.
17.
18.
19.
V. A. Sanin and A. F. Grapov, Pesticides. Handbook [in Russian], Tekhnika. Kiev (1985), p. 68.
O. Shigeru, J. Am. Chem. Soc., 78, 4030 (1956).
F. Thurkauf, A. E. Jacobson, and K. C. Rice, Synthesis, 233 (1998).
F. A. J. Meskens, Synthesis, 501 (1981).
T. W. Bentley, R. V. Jones, and P. J. Wareham, Tetrahedron Lett., 30, 4013 (1989).
M. Sharshunova, V. Shvarts, and Ch. Mikhalets, Thin-Layer Chromatography in Pharmacy and Clinical
Biochemistry [Russian translation], Vol. 2, Mir, Moscow (1980), p. 583.
993