One-pot synthesis of 2-(2-alkoxy-5-amino-4-cyano-2-methylfuran-3(2H)- ylidene)malononitriles

Article abstract of DOI:10.1007/s10593-009-0388-2

A new preparative method was developed for the synthesis of 2-(2-alkoxy-5-amino-4-cyano-2-methyl-3(2H)-ylidene)malononitriles in a single stage from readily obtainable reagents.

Full text of DOI:10.1007/s10593-009-0388-2

Chemistry of Heterocyclic Compounds, Vol. 45, No. 9, 2009
ONE-POT SYNTHESIS OF 2-(2-ALKOXY-
5-AMINO-4-CYANO-2-METHYLFURAN-
3(2H)-YLIDENE)MALONONITRILES
I. N. Bardasov1*, O. V. Kayukova1, Ya. S. Kayukov1, O. V. Ershov1,
M. Yu. Belikov1, and O. E. Nasakin1
A new preparative method was developed for the synthesis of 2-(2-alkoxy-5-amino-4-cyano-2-methyl-
3(2H)-ylidene)malononitriles in a single stage from readily obtainable reagents.
Keywords: dihydrofurans, enamino nitriles, tetracyanocyclopropanes, multicomponent reaction, one-
pot synthesis.
At present multicomponent systems have begun to be used ever more widely for the synthesis of various
heterocyclic systems [1, 2]. Their advantages are a decrease in the amount of solvents used and an increase in
the yields of the targeted compounds on account of the reduction in the number of stages in the synthesis.
Moreover, the development of convenient methods of production has stimulated research into the reactivity of
previously not readily obtainable compounds. We have developed a single-stage method for the synthesis of
2-(2-alkoxy-5-amino-4-cyanofuran-3(2H)-ylidene)malononitriles [3]. On account of the laborious nature of their
production and the high cost of the reagents in the previously developed method of synthesis [3] their chemical
properties have remained practically uninvestigated. The presence of the enamino nitrile and ylidene-
malononitrile fragments in their structure makes it possible to use them as starting compounds in the synthesis of
complex heterocyclic structures. In addition, the appearance of biological activity is possible in these
compounds since representatives exhibiting anti-inflammatory and antimicrobial activity are known among
compounds of the dihydrofuran series [4-8].
The main point of the method that we developed is the reaction of methylglyoxal 1, malononitrile,
monobromomalononitrile, and an aliphatic alcohol 2, which also acts as solvent. In the course of the reaction
2-(2-alkoxy-5-amino-4-cyano-2-methylfuran-3-(2H)-ylidene)malononitriles 4a-h are formed in one
technological stage with yields of 53-69% (Table 1).
We established that the transformations take place through the formation of 3-acetylcyclopropane-
1,1,2,2-tetracarbonitrile (3) [9], which was isolated from the reaction mixture with small yields and identified on
the basis of data from IR spectroscopy and mass spectrometry.
_______
* To whom correspondence should be addressed, e-mail: bardasov.chem@mail.ru.
1I. N. Ul'yanov Chuvash State University, Cheboksary 428015, Chuvash Republic, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1297-1300, September, 2009.
Original article submitted October 30, 2008.
0009-3122/09/4509-1035©2009 Springer Science+Business Media, Inc.
1035

CN
O
NC
NC
NC
Me
CN
O
ROH
2a–h
CN
CN
CN
CN
CN
CN
Me
O
Br
+
+
Me
H
–H2O, –HBr
NH2
O
RO
H
1
4a–h
3
2,4 a R = Pr, b R = i-Pr, c R = Bn, d R = Et, e R = i-Bu, f R = s-Bu, g R = n-Bu, h R = Me
The formation of compound 3 at the intermediate stage is probably similar to the formation of
3-aroylcyclopropane-1,1,2,2-tetracarbonitrile, a method for the synthesis of which we developed earlier [10].
The reaction of the cyclopropane 3 isolated from the reaction mixture with the alcohols 2a-h also leads to the
formation of the dihydrofurans 4a-h with yields of 58-72% (Table 1).
NH
CN
RO OH
Me
O
RO
Me
CN
CN
2a–h
CN
CN
3
4a–h
H
H
NC
NC
A
B
The reaction mechanism may include attack by the alcohols on the carbonyl group of cyclopropane with
the formation of the hemiketal A. This is then followed by intramolecular heterocyclization with participation of
the sterically close hydroxyl and cyano groups and the formation of the furan ring of the intermediate B. The
final compound 4 is formed as a result of subsequent opening of the three-membered ring.
In the IR spectra of compounds 4 there are strong bands of stretching vibrations characteristic of the
conjugated cyano groups in the region of 2216-2218, for the C=C bond of the dicyanomethylene fragment in the
region of 1688-1695, and two broad bands in the regions of 3108-3150 and 3257-3288 cm−1 characteristic of the
amino group. The structures of the synthesized compounds were supported by data from the IR, 1H NMR (Table 2),
and mass spectra.
TABLE 1. Data from Elemental Analysis, Melting Points, and Yields of
Compounds 4a-h
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield, %
mp, °С
C
H
N
A
B
4a
4b
4c
C12H12N4O2
C12H12N4O2
C16H12N4O2
C11H10N4O2
C13H14N4O2
C13H14N4O2
C13H14N4O2
C10H8N4O2
59.12
59.01
59.16
59.01
65.63
65.75
57.32
57.39
60.40
60.45
60.41
60.45
60.52
60.45
55.51
55.55
4.87
4.95
4.88
4.95
4.09
4.14
4.28
4.38
5.39
5.46
5.42
5.46
5.47
5.46
3.68
3.73
22.79
22.94
22.88
22.94
19.05
19.17
24.27
24.34
21.56
21.69
21.62
21.69
21.62
21.69
25.95
25.91
184
188
237
182
185
190
188
240
67
62
53
66
62
69
67
69
72
66
58
78
67
65
64
83
C4d
4e
4f
4g
4h
1036

TABLE 2. Spectral Characteristics of Compounds 4a-h
IR spectrum,
Mass
Com-
ν, cm–1
1H NMR spectrum, δ, ppm (J, Hz)
spectrum,
pound (N–H, C≡N,
С=C)
m/z [M]+
4a
4b
3272, 3136,
2216, 1690
10.18 (1Н, s, NH2); 10.12 (1Н, s, NH2);
3.37 (2Н, m, OCH2CH2CH3); 1.78 (3Н, s, CH3);
1.56 (2Н, m, OCH2CH2CH3);
244
244
0.9 (3Н, t, J = 7.3, OCH2CH2CH3)
3274, 3137,
2216, 1688
10.20 (1Н, s, NH2); 10.13 (1Н, s, NH2);
3.85 (1Н, m, OCH(CH3)2); 1.78 (3Н, s, CH3);
1.20 (3Н, d, J = 6.1, CH3), 1.14 (3Н, d, J = 6.1, CH3)
4c
3276, 3131,
2215, 1693
10.27 (1Н, s, NH2); 10.23 (1Н, s, NH2); 7.37 (5H, m, C6H5);
4.50 (2Н, m, OCH2C6H5); 1.84 (3Н, s, CH3)
292
230
4d
3258, 3112,
2217, 1693
10.20 (1Н, s, NH2); 10.15 (1Н, s, NH2);
3.46 (2Н, m, OCH2CH3); 1.77 (3Н, s, CH3);
1.17 (3Н, t, J = 6.7, OCH2CH3)
4e
4f
3283, 3143,
2216, 1688
10.18 (1Н, s, NH2); 10.12 (1Н, s, NH2);
3.18 (2Н, m, OCH2CH(CH3)2); 1.80 (3Н, s, CH3);
1.80 (1Н, m, OCH2CH(CH3)2); 0.9 (3Н, d, J = 6.7, CH3);
0.89 (3Н, d, J = 6.7, CH3)
258
258
258
3283, 3153,
2216, 1689
10.19 (1Н, s, NH2); 10.12 (1Н, s, NH2);
3.7 (1Н, m, OCH(CH3)CH2CH3); 1.80 (3Н, s, CH3);
1.51 (2Н, m, CH2CH3); 1.12 (3Н, d, J = 6.1, CH3);
0.85 (3Н, t, J = 6.4, CH2CH3)
4g
3282, 3136,
2216, 1689
10.18 (1Н, s, NH2); 10.12 (1Н, s, NH2);
3.40 (2Н, m, OCH2CH2CH2CH3); 1.77 (3Н, s, CH3);
1.52 (2Н, m, OCH2CH2CH2CH3);
1.36 (2Н, m, OCH2CH2CH2CH3);
0.88 (3Н, t, J = 7.4, OCH2CH2CH2CH3)
4h
3263, 3109,
2221, 1695
10.19 (2Н, s, NH2); 3.32 (3Н, s, OCH3); 1.77 (3Н, s, CH3)
216
Thus, we have developed a new preparative method for the synthesis of 2-(2-alkoxy-5-amino-4-cyano-
2-methylfuran-3(2H)-ylidene)malononitriles 4a-h and have proposed a possible mechanism for the reaction.
EXPERIMENTAL
The reactions and the purity of the synthesized substances were monitored by TLC on Silufol UV-254
plates (development in UV light, with iodine vapor, and by thermal decomposition). The IR spectra were
recorded in vaseline oil on an FSM-1202 Fourier spectrometer. The 1H NMR spectra were obtained on a Bruker
DRX-500 spectrometer (500 MHz) in DMSO-d6 with TMS as internal standard. The mass spectra were obtained
on a Shimadzu GCMS-QP 2010S DI instrument (EI 70 eV).
Monobromomalononitrile. To a solution of malononitrile (6.6 g. 0.1 mol) in a mixture of water (20 ml)
and 2-propanol (20 ml) with vigorous stirring we added in small portions bromine (16 g, 0.1 mol). The
temperature of the reaction mixture was kept in the range of 20-25°C, the mixture was stirred for a further
15 min, and it was then left at 0°C for 10 h. The precipitate that separated was filtered off and washed with cold
water.
2-(2-Alkoxy-5-amino-4-cyano-2-methylfuran-3(2H)-ylidene)malononitrile 4a-h (General Method). A.
To a solution of methylglyoxal 1 (0.72 g, 0.01 mol) in aliphatic alcohol (20 ml) with stirring we added in one
portion malononitrile (0.66 g, 0.01 mol) and after it had completely dissolved monobromomalononitrile (1.45 g,
0.01 mol). After some time a precipitate separated, and it gradually dissolved. The mixture was left covered
1037

until the cyclopropane had completely disappeared. It was then evaporated, and 10 ml of water was added. The
precipitate was filtered off and washed with water. The product was purified by reprecipitation from the
respective alcohol with water.
B. A mixture 3-acetylcyclopropane-1,1,2,2-tetracarbonitrile (1.88 g, 0.01 mol) and aliphatic alcohol
2a-h (20 ml) was boiled for 3 h. It was then evaporated to dryness, water (10 ml) was added, and the precipitate
was filtered off and washed with water.
3-Acetylcyclopropane-1,1,2,2-tetracarbonitrile (3). To a solution of methylglyoxal 1 (0.72 g,
0.01 mol) in aliphatic alcohol (20 ml) with stirring we added in one portion malononitrile (0.66 g, 0.01 mol) and
after it had completely dissolved monobromomalononitrile (1.45 g, 0.01 mol). The precipitate that separated
after a short time was filtered off and washed with alcohol and with water, and compound 3 was obtained; mp
184°C. IR spectrum, ν, cm−1: 3059, 2265, 1730. Mass spectrum, m/z: 184 [M]+.
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