Cyclocondensation of 3-acetylfuran-2(5H)-ones with benzylidenemalononitrile. Synthesis of 3-(5-amino-4,6-dicyanobiphenyl-3-yl)furan-2(5H)-ones

Full text of DOI:10.1134/S1070428015120313

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 12, pp. 1809–1812. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © R.M. Hakobyan, S.S. Hayotsyan, G.S. Melikyan, 2015, published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51, No. 12,
pp. 1842–1845.
SHORT
COMMUNICATIONS
Cyclocondensation of 3-Acetylfuran-2(5H)-ones
with Benzylidenemalononitrile. Synthesis of 3-(5-Amino-
4,6-dicyanobiphenyl-3-yl)furan-2(5H)-ones
R. M. Hakobyana, S. S. Hayotsyana, and G. S. Melikyanb
a Institute of Organic Chemistry, Scientific Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of Armenia, pr. Azatutyan 26, Yerevan, 0014 Armenia
e-mail: sargis@hayotsyan.com
b Yerevan State University, Alex Manoogian 1, Yerevan, 0025 Armenia
Received June 19, 2015
DOI: 10.1134/S1070428015120313
3,4-Disubstituted furan-2(5H)-one fragment is
present in many natural biologically active com-
pounds. In particular, furan-2(5H)-one derivatives con-
taining nonidentical aromatic substituents in positions
3 and 4 of the furan ring exhibit various biological
activities [1]. An example is the anti-inflammatory
drug Rofecoxib [4-(4-methanesulfonylphenyl)-3-phe-
nylfuran-2(5H)-one]. Eutypoid A isolated from the
marine mangrove fungus Eutypa sp. (# 424) [2] and
gymnoascolides [3] isolated from the Australian soil
ascomycetes Gimnoascus reessii and Malbranchea
filamentosa IFM41300 are naturally occurring 3,4-di-
substituted furan-2(5H)-ones.
We have previously [4–8] synthesized unsaturated
γ-lactones bearing heteroaromatic substituents in the
3-position of the lactone ring and revealed biological
activity of benzimidazolyl-, benzothiazolyl-, and benz-
oxazolyl-substituted furan-2-ones. In the present
article we report the synthesis of dihydrofuranones
containing a 5-amino-4,6-dicyanobiphenyl-3-yl sub-
stituent on C3. Cyclocondensation of α-hydroxy
ketones 1–4 with ethyl acetoacetate in the presence of
sodium ethoxide [9–11] gave the corresponding
4,5,5-trisubstituted 3-acetylfuran-2(5H)-ones 5–8
which reacted with malononitrile according to
Knoevenagel (by heating in boiling benzene in the
Scheme 1.
Me
Me
NCCH2CN
NH4OAc/AcOH
reflux, 12 h
CN
CN
OH
NaOEt/EtOH
reflux, 20–30 h
R'
R'
O
O
O
R
R
R'
+
–H2O
R
R
Me
OEt
O
O
O
O
O
R
R
1–4
5–8
9–12
CN
CN
Ph
Ph
CN
Ph
CN
CN
CN
NH
PhCH=C(CN)2 (13)
EtOH, piperidine
CN
NH2
R'
R'
R'
–HCN
CN
CN
R
R
R
O
O
O
O
O
O
R
R
R
14–17
1, 5, 9, R = R′ = Me; 2, 6, 10, R = Me, R′ = Ph; 3, 7, 11, RR = (CH2)5, R′ = Me; 4, 8, 12, RR = (CH2)5, R′ = Ph.
1809

HAKOBYAN et al.
1810
Scheme 2.
Ph
CN
Me
EtOH, piperidine
12 h, reflux
Me
O
NH2
+
PhCHO + NCCH2CN
Me
Me
Me
CN
O
O
Me
Me
O
O
5
14
presence of ammonium acetate and glacial acetic acid
with simultaneous removal of liberated water) [12] to
afford 3-(1,1-dicyanoprop-1-en-2-yl) derivatives 9–12
in high yields (Scheme 1).
drous ethanol was heated under reflux. When the reac-
tion was complete, a part of the solvent was distilled
off, and the residue was neutralized with dilute (1:1)
hydrochloric acid and extracted with methylene chlo-
ride. The organic phase was washed with brine and
dried over anhydrous sodium sulfate. The solvent was
distilled off, and the residue was distilled under re-
duced pressure to isolate 3-acetyl-4,5,5-trimethylfuran-
2(5H)-one (5) [5], 3-acetyl-5,5-dimethyl-4-phenylfur-
an-2(5H)-one (6) [7], 3-acetyl-4-methyl-5,5-penta-
methylenefuran-2(5H)-one (7) [6], or 3-acetyl-5,5-
pentamethylen-4-phenylfuran-2(5H)-one (8) [6].
Ethylidenemalononitriles 9–12 possess an activated
methyl group. It is known that ylidenemalononitriles
can be converted into polyfunctionalized benzene
derivatives [13, 14]. Compounds 9–12 were brought
into reaction with benzylidenemalononitrile (13). The
reaction involved initial Michael addition of the ac-
tivated methyl group to the conjugated double bond of
benzylidenemalononitrile, and the adduct thus formed
underwent intramolecular cyclization, followed by
aromatization via elimination of hydrogen cyanide. As
a result, compounds 14–17 were obtained.
Compounds 9–12 (general procedure). 3-Acetyl-
furan 5–8 and 1.1 equiv of malononitrile were dis-
solved in toluene, 0.1 equiv of glacial acetic acid and
0.1 equiv of ammonium acetate were added, and the
mixture was heated under reflux in a flask equipped
with a Dean–Stark trap until water no longer separated.
When the reaction was complete, a solution of sodium
hydrogen carbonate was added, the organic phase was
separated, and the aqueous phase was extracted with
ethyl acetate (3×25 mL). The extracts were combined
with the organic phase and dried over sodium sulfate,
the solvent was distilled off, and the residue crystal-
lized and was washed with hexane–diethyl ether (3:1).
Ethylidenemalononitriles 9–12 and benzylidene-
malononitrile (13) are formed in Knoevenagel reac-
tions whose conditions are similar to those of the con-
densation of 9–12 with 13. Therefore, we performed
three-component reaction of 3-acetylfuranone 5 with
benzaldehyde and 2 equiv of malononitrile in boiling
ethanol in the presence of piperidine [17, 18] and
isolated compound 14 in 32% yield (Scheme 2). The
yield of 14 in the cyclocondensation of 9 with 13,
calculated on the initial 3-acetylfuranone 5, was almost
the same. Taking into account that the three-com-
ponent procedure does not require preliminary prepara-
tion and isolation of 9 and 13, it may by regarded as
an alternative short-cut version of synthesis of 14.
2-[1-(4,5,5-Trimethyl-2-oxo-2,5-dihydrofuran-3-
yl)ethylidene]malononitrile (9) was synthesized from
3.66 g (0.02 mol) of 5 and 1.32 g (0.02 mol) of
malononitrile in 20 mL of toluene in the presence of
0.2 g (0.0022 mol) of ammonium acetate and 0.6 mL
of glacial acetic acid. Yield 2.4 g (56%), white crystals,
mp 112–114°C; published data [12]: mp 115°C. IR
spectrum, ν, cm–1: 2215 (CN), 1740 (C=O), 1640
In summary, we have developed a convenient
procedure for the synthesis of furan-2(5H)-ones with
a 5-amino-4,6-dicyanobiphenyl-3-yl substituent in po-
sition 3 of the furan ring by reaction of 3-(1,1-dicy-
anoprop-1-en-2-yl)furan-2(5H)-ones with benzylidene-
malononitrile or three-component condensation of
3-acetyl-4,5,5-trimethylfuran-2(5H)-one with benzal-
dehyde and malononitrile.
1
(C3=C4), 1569 (C=C). H NMR spectrum, δ, ppm:
1.53 s (6H, 5-CH3), 2.13 s (3H, 4-CH3), 2.52 s (3H,
CH3). 13C NMR spectrum, δC, ppm: 12.81 (4-CH3),
21.54 (CH3), 23.94 (5-CH3), 86.36 (C5), 88.64
[C(CN)2], 110.82 (CN), 110.99 (CN), 122.82 (C3),
166.19 (C4), 167.39 (C=O), 171.97 (CH3C=).
Compounds 5–8 (general procedure). A solution of
equimolar amounts of hydroxy ketone 1–4 and ethyl
acetoacetate and 0.1 equiv of sodium ethoxide in anhy-
2-[1-(5,5-Dimethyl-2-oxo-4-phenyl-2,5-dihydro-
furan-3-yl)ethylidene]malononitrile (10) was synthe-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 12 2015

CYCLOCONDENSATION OF 3-ACETYLFURAN-2(5H)-ONES
1811
sized from 1.15 g (0.005 mol) of 6 and 0.33 g
(0.005 mol) of malononitrile in 10 mL of toluene in the
presence of 0.1 g (0.0011 mol) of ammonium acetate
and 0.5 mL of glacial acetic acid. Yield 0.56 g (41%),
light yellow crystals, mp 92–94°C. IR spectrum, ν,
cm–1: 2213 (CN), 1722 (C=O), 1605 (C=Carom), 1562
(C=C). 1H NMR spectrum, δ, ppm: 1.65 s (6H, 5-CH3),
2.48 s (3H, CH3), 7.33–7.38 m (2H) and 7.49–7.55 m
(3H) (Ph). 13C NMR spectrum, δC, ppm: 22.07 (CH3),
24.62 (5-CH3), 86.80 (C5), 89.05 [C(CN)2], 110.56
(CN), 110.65 (CN), 124.16 (C3), 127.09 (2C, Carom),
128.79 (2C, Carom), 129.46 and 130.20 (Ci, Cp), 165.57
(C4), 167.32 (C=O), 171.61 (CH3C=). Found, %:
C 72.68; H 5.18; N 10.37. C17H14N2O2. Calculated, %:
C 73.37; H 5.07; N 10.07.
Compounds 14–17 (general procedure). A solution
of equimolar amounts of compound 9–12 and benzyli-
denemalononitrile (13) and 0.05 mL of piperidine in
anhydrous ethanol was heated for 4 h under reflux. The
mixture was cooled, and the precipitate was filtered
off, washed with diethyl ether, and recrystallized from
ethanol.
3-Amino-5-(4,5,5-trimethyl-2-oxo-2,5-dihydro-
furan-3-yl)-1,1′-biphenyl-2,4-dicarbonitrile (14).
a. Compound 14 was synthesized according to the
general procedure from 0.6912 g (0.0032 mol) of 9 and
0.5 g (0.0032 mol) of 13 in 16 mL of ethanol in the
presence of 0.05 mL of piperidine. Yield 0.76 g (62%),
light brown crystals, mp 235–237°C. IR spectrum, ν,
cm–1: 3480, 3381 (NH2); 2200 (CN), 1721 (C=O),
1
1635 (C3=C4), 1520 (C=Carom). H NMR spectrum, δ,
2-[1-(4-Methyl-2-oxo-1-oxaspiro[4.5]dec-3-en-
3-yl)ethylidene]malononitrile (11) was synthesized
from 4.16 g (0.02 mol) of 7 and 1.4 g (0.033 mol) of
malononitrile in 40 mL of toluene in the presence of
1.2 g (0.013 mol) of ammonium acetate and 2 mL of
glacial acetic acid. Yield 3.95 g (77%), white crystals,
mp 143–145°C. IR spectrum, ν, cm–1: 2210 (CN),
ppm: 1.56 s (6H, 5-CH3), 2.09 s (3H, 4-CH3), 6.57 br.s
(2H, NH2), 6.69 s (1H, Harom), 7.46–7.60 m (5H, Ph).
13C NMR spectrum, δC, ppm: 24.78 (2C, CH3), 86.09
(C5), 95.28 (CCN), 95.50 (CCN), 114.32 (CN), 114.98
(CN), 118.89 (CHarom), 124.96 (C3), 127.31 (2C),
127.96 (2C), 128.08 (2C), 128.34 (2C), 128.85
(CHarom), 129.29 (CHarom), 130.29, 136.90, 138.86 (Ci),
49.14 (CNH2), 153.03 (Ci), 167.72 (C4), 169.32 (C=O).
Found, %: C 71.37; H 5.07; N 12.47. C21H17N3O2.
Calculated, %: C 73.45; H 4.99; N 12.24.
1
1721 (C=O), 1625 (C3=C4), 1561 (C=C). H NMR
spectrum, δ, ppm: 1.24–1.41 m (1H), 1.52–1.60 m
(2H), and 1.63–1.90 m (7H) (C5H10); 2.11 s (3H,
4-CH3), 2.51 s (3H, CH3). 13C NMR spectrum, δC,
ppm: 13.10 (4-CH3), 21.27 (2C, CH2), 21.62 (CH3),
23.72 (CH2), 32.53 (2C, CH2), 88.01 (C5), 88.62
[C(CN)2], 110.88 (CN), 111.05 (CN), 123.01 (C3),
166.33 (C4), 167.53 (C=O), 171.95 (CH3C=). Found,
%: C 70.95; H 6.32; N 11.12. C15H16N2O2. Calculated,
%: C 70.29; H 6.29; N 10.93.
b. A solution of 5 mmol (0.64 g) of 5, 11 mmol
(0.72 g) of malononitrile, 5 mmol (0.53 g) of benzalde-
hyde, and 0.3 mL of piperidine in 30 mL of anhydrous
ethanol was heated for 12 h under reflux. The mixture
was cooled, and the precipitate was filtered off,
washed with diethyl ether, and recrystallized from
ethanol. Yield 32%.
2-[1-(2-Oxo-4-phenyl-1-oxaspiro[4.5]dec-3-en-
3-yl)ethylidene]malononitrile (12) was synthesized
from 2.7 g (0.01 mol) of 8 and 0.66 g (0.01 mol) of
malononitrile in 10 mL of toluene in the presence of
0.08 g (0.00087 mol) of ammonium acetate and
0.5 mL of glacial acetic acid. Yield 1.76 g (55%),
white crystals, mp 113–115°C. IR spectrum, ν, cm–1:
2214 (CN), 1727 (C=O), 1620 (C=Carom), 1562 (C=C).
1H NMR spectrum, δ, ppm: 1.14–1.30 m (1H) and
1.70–1.87 m (9H) (C5H10), 2.44 s (3H, CH3), 7.27–
7.32 m (2H) and 7.47–7.53 m (3H) (Ph). 13C NMR
spectrum, δC, ppm 21.35 (2C), 22.17, 23.66, 32.75
(2C), 88.48 (C5), 89.03 [C(CN)2], 110.42 and 110.65
(2C, CN), 125.03 (C3), 126.93 (2C, Carom), 128.58
(2C, Caromr), 129.73 and 129.78 (Ci, Cp), 165.57 (C4),
167.18 (C=O), 171.87 (CH3C=). Found, %: C 73.21;
H 5.52; N 8.95. C20H18N2O2. Calculated, %: C 75.45;
H 5.70; N 8.80.
3-Amino-5-(5,5-dimethyl-2-oxo-4-phenyl-2,5-di-
hydrofuran-3-yl)-1,1′-biphenyl-2,4-dicarbonitrile
(15) was synthesized from 0.278 g (0.001 mol) of 10
and 0.154 g (0.001 mol) of 13 in 5 mL of ethanol in the
presence of 0.05 mL of piperidine. Yield 0.28 g (69%),
yellow crystals, mp 212–214°C. IR spectrum, ν, cm–1:
3415, 3325 (NH2); 2200 (CN), 1702 (C=O), 1615
1
(C3=C4), 1525 (C=Carom). H NMR spectrum, δ, ppm:
1.67 s (6H, CH3), 6.46 br.s (2H, NH2), 6.70 s (1H,
Harom), 7.25–7.35 m (2H) and 7.38–7.45 m (3H) (Ph),
7.45–7.47 br.m (5H, Ph). Found, %: C 75.07; H 4.89;
N 10.55. C26H19N3O2. Calculated, %: C 77.02; H 4.72;
N 10.36.
3-Amino-5-(4-methyl-2-oxo-1-oxaspiro[4.5]dec-
3-en-3-yl)-1,1′-biphenyl-2,4-dicarbonitrile (16) was
synthesized from 0.256 g (0.001 mol) of 11 and 0.154 g
(0.001 mol) of 13 in 5 mL of ethanol in the presence of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 12 2015

HAKOBYAN et al.
1812
0.05 mL of piperidine. Yield 0.22 g (57%), brown
crystals, mp 255–257°C. IR spectrum, ν, cm–1: 3451,
3345 (NH2); 2205 (CN), 1720 (C=O), 1645 (C3=C4),
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(3H, 4-CH3), 6.56 br.s (2H, NH2), 6.66 s (1H, Harom),
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 12 2015