Synthesis of 6-amino-4-aryl- 2R-4H-furo[2,3-b]pyran-5-carbo- nitriles based on the condensation of 3-arylmethylene-3H-furan-2-ones with malononitrile

Article abstract of DOI:10.1007/s10593-009-0335-2

Methods were developed for the synthesis of 6-amino-4-aryl-2R-4H-furo[2,3- b]pyran-5-carbonitriles based on the reaction of 3-arylmethylene-3H-furan-2-ones with malononitrile and also using a multicomponent reaction. The reaction schemes are discussed.

Full text of DOI:10.1007/s10593-009-0335-2

Chemistry of Heterocyclic Compounds, Vol. 45, No. 6, 2009
SYNTHESIS OF 6-AMINO-4-ARYL-
2R-4H-FURO[2,3-b]PYRAN-5-CARBO-
NITRILES BASED ON THE CONDENSATION
OF 3-ARYLMETHYLENE-3H-FURAN-2-ONES
WITH MALONONITRILE
T. V. Aniskova1* and A. Yu. Yegorova1
Methods were developed for the synthesis of 6-amino-4-aryl-2R-4H-furo[2,3-b]pyran-5-carbonitriles
based on the reaction of 3-arylmethylene-3H-furan-2-ones with malononitrile and also using a
multicomponent reaction. The reaction schemes are discussed.
Keywords: 3-arylmethylene-3H-furan-2-ones, substituted furo[2,3-b]pyran-5-carbonitriles, malono-
nitrile, Michael condensation.
The ability of 3-arylmethylene-3H-furan-2-ones to take part in Michael condensation as acceptors was
used earlier in the reaction with cyclohexanone [1], acetylacetone [2], and acetoacetic ester [3].
In a continuation of investigations into the reactivity of 3-arylmethylene-3H-furan-2-ones with
methylene-active compounds their behavior in reaction with malononitrile was studied.
The presence of the highly reactive methylene and cyano groups in malononitrile makes it possible to
use this compound as a reagent for cyclizations leading to the formation of carbo- and heterocyclic compounds.
The reaction of 5-aryl-3-arylmethylene-3H-furan-2-ones 1-4 with malononitrile was realized by heating
the reagents in solution in DMSO in a molar ratio of 1:1 in the presence of catalytic amounts of triethylamine.
Cl
Cl
CN
DMSO
Et3N
CN
CN
+
R
NH2
O
O
O
R
O
1–4
5–8
1, 5 R = C5H11; 2, 6 R = Ph; 3, 7 R = p-Tol; 4, 8 R = 3-MeOC6H4
_______
* To whom correspondence should be addressed, e-mail: aniskovatv@mail.ru.
1 N. G. Chernyshevskii Saratov State University, Saratov 410012, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 836-840, June, 2009. Original
article submitted October 13, 2008.
662
0009-3122/09/4506-0662©2009 Springer Science+Business Media, Inc.

TABLE 1. The Physicochemical Characteristics of the Michael
Condensation Products 5-8
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield, %
(method)
mp, °C
С
Н
N
5
6
С19H19ClN2O2
С20H13ClN2O2
66.45
66.57
68.48
68.87
5.50
5.59
3.39
3.76
8.35
8.17
8.51
8.03
105-107
122-124
70
63 (A)
73 (B)
58 (C)
65 (A)
80 (B)
63 (C)
68
7
8
С21H15ClN2O2
С21H15ClN2O3
69.46
69.52
4.43
4.17
7.26
7.72
145-147
153-155
66.23
66.58
4.32
3.99
7.54
7.40
6-Amino-4-aryl-2R-4H-furo[2,3-b]pyran-5-carbonitriles 5-8 were isolated with yields of up to 70%
(Table 1). The IR spectra of compounds 5-8 contain stretching vibrations in the region of 2240-2220 (CN),
3450-3400 (NH2), and 3160-3155 cm−1 (vibrations of the furan ring). The 1H NMR spectra contain the following
characteristic signals: A singlet at 6.41-6.45 for the proton of the furan ring; a signal in the downfield region at
6.97-7.20 (2H, br. s) for the protons of the amino group; a singlet at 4.97-4.80 ppm for the proton at the tertiary
carbon atom H-4. The protons of the aromatic substituents appear as a series of signals at 7.26-7.75 ppm
(Table 2).
The reaction of 5-aryl-3-arylmethylene-3H-furan-2-ones 1-4 with malononitrile in the presence of an
organic base (triethylamine) is of the cascade heterocyclization type (path A). The carbanion of malononitrile is
generated under the conditions of base catalysis and then adds at the exocyclic C=C bond with the formation of
Michael adducts. Subsequent nucleophilic addition of the hydroxy group of the furan ring to the cyano group of
the side chain leads to the cyclization products 6-amino-4-aryl-2R-4H-furo[2,3-b]pyran-5-carbonitriles 5-8.
The furo[2,3-b]pyran-5-carbonitriles in turn are polyfunctional compounds having high chemical
activity and various biological effects, giving rise to the prospect of finding and developing effective methods
for the synthesis of compounds of this series.
In this connection we developed alternative methods based on the use of 5-R-3H-furan-2-ones 9 and 10
as Michael condensation addends. They are polyfunctional compounds, making them promising for targeted
organic synthesis in various types of reactions, including tandem reactions. Furan-2-ones behave as CH acids
under the conditions of base catalysis and are capable of acting as addends in the Michael reaction with
TABLE 2. The 1H NMR Spectra of Compounds 5-8
Chemical shifts, δ, ppm
Com-
pound
Furyl
(1Н, s)
CH-Ar
(1Н, s)
NH2
Ar
R
CH3
(2Н, s)
(4Н, m)
5
6
6.00
6.41
4.74
4.97
6.98
7.04
7.05-7.15
7.26-7.45
1.31-2.35
(11H, m)
—
—
7.34-7.65
(5Н, m)
7
8
6.45
6.40
4.80
4.88
7.20
7.15
7.30-7.50
6.90-7.17
7.39-7.53
(4Н, m)
2.35
3.73
7.43-7.56
(4Н, m)
663

Ar
Ar
Ar
CN
CN
(Et)3N
CN
CN
+
O
R
O
R
O
O
1–4
Ar
O
Ar
O
CN
CN
CN
CN
NH
Path A
R
OH
R
O
R
NH2
O
O
5–8
α,β-unsaturated compounds like unsaturated nitriles. We studied the reaction of unsubstituted 5-R-3H-furan-
2-ones 9 and 10 with the unsaturated nitrile 11, which was produced by the reaction of an aromatic aldehyde in a
1:1 molar ratio with malononitrile in DMSO in the presence of triethylamine. The reaction begins with Michael
addition of the furan-2-ones 9 and 10 at the activated double bond of the unsaturated nitrile 11, followed by
nucleophilic attack at the carbon atom of the cyano group, leading to the formation of a pyran ring and the
formation of compounds 6 and 7 (path B).
Cl
CN
CN
11
Path B
O
Cl
H
CN
CN
O
6, 7
R
O
+
9, 10
12
Path C
9 R = Ph; 10 R = p-Tol
Multicomponent cascade reactions are of particular interest as methods for the synthesis of
polyfunctional carbo- and heterocyclic compounds. The substrates used in the three-component condensation
contain several reaction centers, making various combinations of paired reactions of all the components possible
(path C).
A Knoevenagel reaction of the aromatic aldehyde 12 with the dinitrile of malonic acid probably takes
place initially, and this is followed by reaction of the furan-2-ones 9 and 10 with the unsaturated nitrile. Further
cyclization leads to 6-amino-4-aryl-2R-4H-furo[2,3-b]pyran-5-carbonitriles 6 and 7.
There is also another reaction path in which the aldehyde 12 reacts with the furan-2-ones 9 and 10 at the
first stage, malononitrile adds to the reaction product, and heterocyclization occurs. We were, however, unable
to isolate the intermediate, and this hinders the choice of initial reaction path.
The physicochemical characteristics of compounds 6 and 7 produced from the (arylmethylene)furan-
2-ones and by the multicomponent reactions fully coincide.
Thus, the reaction of 5-R-3-arylmethylene-3H-furan-2-ones with malononitrile was studied. As a result
products containing nitrile and amino groups are formed, and they open up paths for further functionalization of
the obtained compounds and are, moreover, valuable biologically active substances in their own right.
664

EXPERIMENTAL
The IR spectra were recorded on an FSM-1201 Fourier spectrometer in tablets with KBr in the region of
400-4000 cm−1. The 1H NMR spectra were obtained in CDCl3 on a Bruker MSL-400 spectrometer (400 MHz) at
20-25°C with TMS as internal standard. Thin-layer chromatography was performed on Silufol UV-254 plates in
the 2:2:1 hexane–ethyl acetate–chloroform system with iodine vapor as developer.
The arylmethylene-substituted 3H-furan-2-ones 1-4 and 5-R-3H-furan-2-ones 9 and 10 were obtained
by the known method [4].
6-Amino-4-aryl-2R-4H-furo[2,3-b]pyran-5-carbonitriles 5-8. A. To a mixture of the arylmethylene-
substituted 3H-furan-2-one 1-4 (0.01 mol) and malononitrile (0.01 mol) we added a few drops of triethylamine
in DMSO solution. The reaction mixture was heated for 4-5 h, poured into cold water, and neutralized with
dilute HCl. The crystals that separated were filtered off and recrystallized from hexane (Tables 1 and 2).
B. To a mixture of 5-R-3H-furan-2-one 9 or 10 (0.01 mol) and the unsaturated nitrile 11 (0.01 mol),
obtained by the method in [5], we added a few drops of triethylamine in DMSO solution. The mixture was
treated similarly to method A.
C. To a mixture of 5-R-3H-furan-2-one 9 or 10 (0.01 mol), the aromatic aldehyde (0.01 mol), and
malononitrile (0.01 mol) we added a few drops of triethylamine in DMSO solution. The mixture was treated
similarly to method A.
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