Reactions of methoxybenzylidene derivatives of 2,2-dimethyl-1,3-dioxane-4, 6-dione and their saturated analogs with certain nucleophilic reagents

Article abstract of DOI:10.1007/s10593-011-0690-7

The reactions of the methoxybenzylidene derivatives of 2,2-dimethyl-1,3- dioxane-4,6-dione and their saturated analogs with potassium hydroxide in methanol, ammonia, and hydrazine hydrate were realized. The 1,2- bis(methoxybenzylidene)hydrazines, amides,

Full text of DOI:10.1007/s10593-011-0690-7

Chemistry of Heterocyclic Compounds, Vol. 46, No. 12, 2011
REACTIONS OF METHOXYBENZYLIDENE DERIVATIVES
OF 2,2-DIMETHYL-1,3-DIOXANE-4,6-DIONE AND THEIR
SATURATED ANALOGS WITH CERTAIN NUCLEOPHILIC
REAGENTS
Z. Tetere1, I. Ravina1, I. Rijkure1, and D. Zicane1*
The reactions of the methoxybenzylidene derivatives of 2,2-dimethyl-1,3-dioxane-4,6-dione and their
saturated analogs with potassium hydroxide in methanol, ammonia, and hydrazine hydrate were
realized. The 1,2-bis(methoxybenzylidene)hydrazines, amides, and hydrazides of methoxybenzylidene-
malonic acid, suitable for use as structural blocks in the synthesis of various structures based on them,
were prepared and characterized.
Keywords: amides, benzylidene derivatives, hydrazides, 2,2-dimethyl-1,3-dioxane-4,6-dione,
methoxybenzaldehydes.
The methoxyphenyl substituent is a structural fragment of a large number of pharmaceutical
preparations, the best known of which are drugs with a stimulating action on the cardiovascular system [1, 2]
and neurotropic activity [3].
As starting materials containing the above-mentioned fragment for the synthesis of new compounds,
unknown in the literature, we chose the methoxybenzylidene derivatives of 2,2-dimethyl-1,3-dioxane-4,6-dione
3 and their saturated analogs 4. Compounds 3 are the products from the condensation of methoxy-substituted
benzaldehydes 1 with 2,2-dimethyl-1,3-dioxane-4,6-dione (isopropylidenemalonate, Meldrum’s acid) (2).
Methods for the production of the 2,5- (3a), 2,4- (3b), and 3,4,5- (3c) methoxybenzylidene derivatives
are known in the literature [4], and the 2,3,4- (3c) and 3,4,5- (3d) methoxy derivatives were obtained by an
analogous procedure.
The hydrogenation of compounds 3 was conducted with sodium borohydride in methanol at room
temperature.
In view of the fact that the 1,3-dioxane ring in isopropylidenemalonates readily undergoes decomposi-
tion with ring opening in reactions with nucleophilic reagents [5-7] we realized the reactions of compounds
3 and 4 with potassium hydroxide in methanol, ammonia (donors of ammonia: ammonium hydroxide and
hexamethyldisilazane), and hydrazine hydrate.
_______
* To whom correspondence should be addressed, e-mail: daina_zi@ktf.rtu.lv.
1Riga Technical University, Riga LV-1007, Latvia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1795-1799, December, 2010.
Original article submitted September 24, 2010.
0009-3122/11/4612-1449©2011 Springer Science+Business Media, Inc.
1449

The experiments showed that compounds 3 and 4 were isolated unchanged during the reactions with
potassium hydroxide even after boiling the reaction components in methanol for 15 h. The initial compounds 3
were also isolated during the reaction of the methoxybenzylidene derivatives with ammonia. The saturated
compounds 4 react both with an aqueous solution of ammonia 6a and with hexamethyldisilazane 6b. The best
yields here were obtained with hexamethyldisilazane 6b, while a few side products were obtained in addition to
the desired products 7 during the reaction with ammonium hydroxide.
O
O
O
O
O
O
O
O
O
O
NaBH4
DMF
O
+
O
O
(MeO)
O
n
(OMe)
(MeO)
n
4a–e
n
2
3a–e
1
NH2
OH
HNR
6a,b
O
N
N
(MeO)
7a–e
n
O
H2NNH2·H2O
(MeO)
4a–e
H
N
3a–e
NH2
H2NNH2·H2O
n
(OMe)
n
5a–e
OH
O
(MeO)
n
8a,b,e
3-8 a 2,5-OMe, b 2,4-OMe; 37 c 2,3,4-OMe, d 3,4,5-OMe; 3-8 e 2,4,5-OMe;
38 a,b n = 2; e n = 3, 37 c,d n = 3; 6 a R = H, b R = Me3Si.
With hydrazine hydrate compounds 3 and 4 form different products. With hydrazine hydrate the
unsaturated compounds 3 form derivatives of bis-benzylidenehydrazines 5. It can be supposed that on account of
the donating effect of the methoxy groups situated in the benzene ring the reaction takes place by a retro-aza-
Claisen mechanism.
With hydrazine hydrate under analogous conditions the saturated compounds 4a,b and 4e form the
corresponding methoxyphenyl-2-hydrazinocarbonylpropionic acids 8a,b and 8e, while compounds 4c and 4d do
not react under these conditions.
All the obtained compounds are of interest not only as potential biologically active substances but also
as active building blocks for the creation of more complex structures based on them.
The composition of the synthesized compounds was confirmed by the results of elemental analysis, and
the structure was confirmed by the 1H NMR spectra, in which the signals for the protons of all the fragments of
the molecules resonate in the characteristic regions.
EXPERIMENTAL
The 1H NMR spectra were obtained on a Bruker 300 instrument (300 MHz) in CDCl3 (compounds 4a-e
and 5a-e) and DMSO-d6 (compounds 7a-e and 8a,b,e) with TMS as internal standard.
The individuality of the synthesized compounds was verified by TLC on Merck silica gel 60 F254 plates
in the solvent systems: chloroform–methanol–glacial acetic acid 95:5:3 (for 4a-e, 7a-e, and 8a,b,e) and ethyl
acetate–ethanol–glacial acetic acid 9:1:1 (for 5a-e).
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5-(2,3,4-Trimethoxy)-2,2-dimethyl- (3c) and 5-(3,4,5-Trimethoxy)-2,2-dimethylbenzylidene-1,3-di-
oxane- 4,6-diones (3d). These compounds were obtained by the method in [4].
Compound 3c. The yield 89%; mp 138-139°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.65 (6H, s, 2CH3);
5.35 (9H, s, 3OCH3); 6.49 (1H, s, arom); 7.49 (1H, s, arom); 8.62 (1H, s, =CH).
Compound 3d. The yield 86%; mp 114-115°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.65 (6H, s, 2CH3);
5.35 (9H, s, 3OCH3); 6.28 (1H, s, arom); 6.55 (1H, s, arom); 8.62 (1H, s, =CH).
5-Mthoxybenzyl-2,2-dimethyl-1,3-dioxane-4,6-diones 4a-e. To a suspension of the compound 3a-e
(0.01 mol) in methanol (30 ml) we added with stirring sodium borohydride (0.018 mol). A few minutes after all
the sodium borohydride had been added the reaction solution became colorless. The mixture was stirred for a
further 1 h and acidified to pH ~2-3 with dilute (1:1) hydrochloric acid. The precipitate was filtered off and
recrystallized from ethanol.
1,2-Bis(p-methoxybenzylidene)hydrazines 5a-e. A mixture of the compound 3a-e (0.01 mol),
hydrazine hydrate (8 ml), and dioxane (30 ml) was stirred at room temperature for 12 h. The dioxane was
distilled, and the residue was dissolved in water and acidified to pH ~3-4 with dilute hydrochloric acid (1:1).
The precipitate was filtered off and recrystallized from ethanol (5a,c-e) or diluted ethanol (1:1) (5b).
TABLE 1. Characteristics of the Synthesized Compounds 4a-e, 5a-e, 7a-e,
and 8a,b,e
Found, %
——————
Calculated, %
Com-
pound
Empirical
Formula
mp,°C
Yield, %
92
С
H
N
4a
C15H18O6
61.13
61.22
6.09
6.16
—
99–100
4b
4c
4d
4e
5a
5b
5c
5d
5e
7a
7b
7c
7d
7e
8a
8b
8e
C15H18O6
C16H20O7
61.41
61.22
59.23
59.25
59.28
59.25
59.35
59.25
65.79
65.84
65.44
65.84
61.58
61.84
61.62
61.84
61.80
61.84
56.87
56.91
56.87
56.91
55.15
55.12
54.62
55.12
55.23
55.12
53.69
53.73
53.43
53.73
6.18
6.16
6.15
6.22
6.40
6.22
6.18
6.22
6.09
6.14
6.10
6.14
6.27
6.23
6.27
6.23
6.20
6.23
5.89
5.97
5.91
5.97
6.12
6.01
5.97
6.01
6.02
6.05
5.94
6.01
5.89
6.01
—
—
—
—
113–115
89-90
85
78
90
85
43
50
48
44
46
89
61
64
65
72
93
86
83
C16H20O7
106-108
128-130
163-165
237-238
210-212
194-195
222-224
150-151
170-171
123-125
158-160
167-168
154-156
156-158
158-160
C16H20O7
C18H20N2O4
C18H20N2O4
C20H24N2O6
C20H24N2O6
C20H24N2O6
C12H15NO5
C12H15NO5
C13H17NO6
C13H17NO6
C13H17NO6
C12H16N2O5
C12H16N2O5
C13H18N2O6
8.50
8.53
8.55
8.53
7.22
7.21
7.24
7.21
7.20
7.21
5.31
5.53
5.43
5.53
5.16
4.94
5.14
4.94
4.83
4.94
10.25
10.44
10.44
10.44
52.02
52.34
5.96
6.08
9.26
9.39
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TABLE 2. 1H NMR Spectra of the Synthesized Compounds 4a-e, 5a-e, 7a-e, 8a,b,e
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
4a
4b
4c
4d
4e
5a
5b
5c
1.75 (3H, s, CH3); 1.79 (3H, s, CH3); 3.38 (2H, d, J = 5.84, CH2);
3.78 (6H, d, J = 3.39, 2OCH3); 4.05 (1H, t, J = 5.84, CH); 6.80 (2H, s, arom); 7.28 (1H, s, arom)
1.71 (3H, s, CH3); 1.76 (3H, s, CH3); 3.33 (2H, d, J = 5.86, CH2);
3.81 (6H, d, J = 3.52, 2OCH3); 3.94 (1H, t, J = 5.86, CH); 6.52 (2H, s, arom); 7.25 (1H, s, arom)
1.73 (3H, s, CH3); 1.78 (3H, s, CH3); 3.34 (2H, d, J = 5.47, CH2);
3.84 (9H, d, J = 6.4, 3OCH3); 3.98 (1H, t, J = 5.47, CH); 6.61 (1H, s, arom); 7.03 (1H, s, arom)
1.50 (3H, s, CH3); 1.73 (3H, s, CH3); 3.44 (2H, d, J = 4.69, CH2); 3.72 (1H, t, J = 4.69, CH);
3.80 (3H, br. s, OCH3); 3.83 (6H, br. s, 2OCH3); 6.56 (2H, s, arom)
1.71 (3H, s, CH3); 1.76 (3H, s, CH3); 3.33 (2H, d, J = 5.47, CH2); 3.80 (3H, d, J = 3.52, OCH3);
3.85 (6H, t, J = 5.81, 2OCH3); 3.93 (1H, t, J = 5.48, CH); 6.49 (1H, s, arom); 6.92 (1H, s, arom)
3.87 (6H, s, 2OCH3); 3.88 (6H, s, 2OCH3); 6.91 (2H, d, J = 9.0, arom);
7.00 (2H, dd, J = 9.0, J = 3.2, arom); 7.68 (2H, d, J = 3.2, arom); 9.10 (2H, s, 2СН=)
3.87 (12H, br. s, 4 OCH3); 6.46 (2H, d, J = 2.3, arom); 6.58 (2H, d, J = 8.2, arom);
8.10 (2H, br. s, arom); 9.06 (2H, s, 2СН=)
3.89 (6H, br. s, 2OCH3); 3.93 (6H, s, 2OCH3); 3.98 (6H, s, 2OCH3);
6.77 (2H, d, J = 8.9, arom); 7.93 (2H, br. s, arom); 9.00 (2H, s, 2СН=)
5d
5e
3.91 (6H, s, 2OCH3); 3.94 (12H, s, 4OCH3); 7.09 (4H, s, arom); 8.57 (2H, s, 2СН=)
3.88 (6H, s, 2OCH3); 3.94 (6H, s, 2OCH3); 3.95 (6H, s, 2OCH3); 6.51 (4H, s, arom);
9.04 (2H, s, 2СН=)
7a
7b
7c
2.87 (1H, dd, J = 14.01, J = 8.6, СН); 2.97 (1H, dd, J = 14.01, J = 6.2, СН);
3.48 (1H, dd, J = 8.6, J = 6.2, СН); 3.66 (3H, s, OCH3); 3.73 (3H, s, OCH3);
6.67 (1H, d, J = 3.1, arom); 6.73 (1H, dd, J = 8.9, J = 3.2, arom); 6.84 (1H, s, NH);
6.86 (1H, d, J = 8.9, arom); 7.41 (1H, s, NH); 12.45 (1H, s, COOH)
2.79 (1H, dd, J = 14.0, J = 8.5, СН); 2.92 (1H, dd, J = 14.0, J = 6.4, СН);
3.43 (1H, dd, J = 8.50, J = 6.40, СН); 3.73 (3H, s, OCH3); 3.76 (3H, s, OCH3);
6.39 (1H, dd, J = 8.1, J = 2.1, arom); 6.49 (1H, d, arom); 6.95 (1H, d, J = 8.1, arom);
6.96 (1H, br. s, NH); 7.37 (1H, br. s, NH); 12.4 (1H, br. s, COOH)
2.85 (1H, dd, J = 14.01, J = 8.5, СН); 2.95 (1H, dd, J = 14.1, J = 6.4, СН);
3.43 (1H, dd, J = 8.60, J = 6.4, СН); 3.73 (3H, s, OCH3); 3.79 (6H, s, 2OCH3);
6.67 (1H, d, J = 8.6, arom); 6.81 (1H, d, J = 8.6, arom); 6.98 (1H, s, NH);
7.43 (1H, s, NH); 12.43 (1H, s, COOH)
7d
2.91 (1H, dd, J = 14.1, J = 8.2, СН); 2.96 (1H, dd, J = 14.1, J = 6.60, СН);
3.49 (1H, dd, J = 8.30, J = 6.6, СН); 3.61 (3H, s, OCH3); 3.73 (6H, s, 2OCH3);
6.51 (2H, br. s, arom); 7.05 (1H, s, NH); 7.46 (1H, s, NH); 12.48 (1H, s, COOH)
7е
2.83 (1H, dd, J = 13.7, J = 8.6, СН); 2.93 (1H, dd, J = 13.70, J = 6.2, СН);
3.43 (1H, dd, J = 8.6, J = 6.6, СН); 3.64 (3H, s, OCH3); 3.75 (6H, s, 2OCH3);
6.63 (1H, s, arom); 6.71 (1H, s, arom); 6.98 (1H, s, NH); 7.37 (1H, s, NH);
12.41 (1H, s, COOH)
8а
8b
8е
2.84 (1H, dd, J = 13.9, J = 8.6, СН); 3.02 (1H, dd, J = 13.9, J = 6.2, СН);
3.28-3.40 (2H, m, NH2); 3.43 (1H, dd, J = 8.60, J = 6.20, СН); 3.65 (3H, s, OCH3);
3.72 (3H, s, OCH3); 6.64 (1H, d, J = 3.0, arom); 6.71 (1H, d, J = 3.0, arom);
6.83 (1H, d, J = 3.0, arom); 6.86 (1H, br. s, NH); 9.22 (1H, s, COOH)
2.79 (1H, dd, J = 13.7, J = 8.6, СН); 2.97 (1H, dd, J = 13.7, J = 6.2, СН);
3.20-3.30 (2H, m, NH2); 3.38 (1H, dd, J = 8.6, J = 6.2, СН); 3.72 (3H, s, OCH3);
3.76 (3H, s, OCH3); 6.37 (1H, d, J = 2.3, arom); 6.39 (1H, d, J = 2.3, arom);
6.49 (1H, d, J = 2.3, arom); 6.93 (1H, s, NH); 9.1 (1H, br. s, COOH)
2.80 (1H, dd, J = 13.7, J = 8.6, СН); 2.96 (1H, dd, J = 13.7, J = 6.2, СН);
3.08-3.22 (2H, m, NH2); 3.37 (1H, dd, J = 8.6, J = 6.2, СН); 3.64 (3H, s, OCH3);
3.75 (6H, s, 2OCH3); 6.62 (1H, s, arom); 6.66 (1H, s, arom); 6.89 (1H, s, NH);
9.11 (1H, s, COOH)
Amides of 2-(p-Methoxybenzyl)malonic acid 7a-e. A mixture of the compound 4a-e (0.01 mol),
hexamethyldisilazane (0.03 mol), and methylene chloride (40 ml) was boiled with stirring for 3 h. The solvent
was distilled, and the residue was dissolved in 30 ml of 2-propanol and stirred until a precipitate formed (~2 h).
The precipitate was filtered off, dissolved in water, and acidified to pH ~2-3 with dilute hydrochloric acid (1:1).
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The product was filtered off and recrystallized from ethanol (7a,b and 7d,e) or a mixture of ethyl acetate and
hexane (1:0.5) (7c).
Hydrazides of 2-(p-Methoxybenzyl)malonic Acid 8a,b,e. A mixture of the compound 4a,b,e (0.01 mol),
hydrazine hydrate (8 ml), and dioxane (30 ml) was stirred at room temperature for 12 h. The reaction products
were isolated under conditions similar to the conditions for the production of the bis products 5a-e. They were
recrystallized from ethanol.
We express our gratitude to Assoc. Prof. M. Turk for rewarding scientific discussions.
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