The use of anilinodihydrofurans in the synthesis of novel heterocyclic compounds

Article abstract of DOI:10.1007/s10593-011-0714-3

Alkyl 4-oxo-2-phenylamino-4,5-dihydrofuran-3-carboxylates were used for the preparation of alkyl 5-amino-7-aryl-2-{[aryl(hydroxy)methyl](phenyl)amino}-4,6- dicyano-1-benzofuran-3-carboxylates, 4-oxo-2-phenylamino-N-(p-tolyl)-4,5- dihydrofuran-3-carboxamid

Full text of DOI:10.1007/s10593-011-0714-3

Chemistry of Heterocyclic Compounds, Vol. 47, No. 1, April, 2011 (Russian Original Vol. 47, No. 1, January, 2011)
THE USE OF ANILINODIHYDROFURANS IN THE
SYNTHESIS OF NOVEL HETEROCYCLIC COMPOUNDS
M. Hammouda1*, Z. M. Abou Zeid1, H. A. Etman1, and M. A. Metwally1**
Alkyl 4-oxo-2-phenylamino-4,5-dihydrofuran-3-carboxylates were used for the preparation of alkyl
5-amino-7-aryl-2-[aryl(hydroxy)methyl](phenyl)amino-4,6-dicyano-1-benzofuran-3-carboxylates,
4-oxo-2-phenylamino-N-(p-tolyl)-4,5-dihydrofuran-3-carboxamide, and ethyl 4-chloro-5-formyl-
2-(phenylamino)furan-3-carboxylate. The latter was used for the synthesis of ethyl 4-chloro-
5-(hydrazinylidenemethyl)-2-(phenylamino)furan-3-carboxylate and diethyl 5,5'-(hydrazine-1,2-di-
ylidenemethylylidene)bis[4-chloro-2-(phenylamino)furan-3-carboxylate].
Keywords: anilinodihydrofurans, benzofurans, substituted furans.
The increasing importance of furano-fused heterocycles as biologically active compounds [1–5] has led
to continuing development of new simple procedures for their synthesis. In the light of these findings and our
continuing interest in the synthetic importance of the enaminones and synthesis of some functionally substituted
heterocycles [6–9], we have investigated the behavior of some furans of the enaminone type towards
cinnamonitriles.
When arylidenemalononitriles 1a–c [10] were subjected to reaction with alkyl 4-oxo-2-phenylamino-
4,5-dihydrofuran-3-carboxylates 2a,b [11] in refluxing 1-propanol in the presence of a catalytic amount of
piperidine (Scheme 1), the 1-benzofuran derivatives 5a–c were obtained, instead of the expected furo-
[3,2-b]pyrans 4a–c. Similar behavior has been reported previously [12–16].
The NMR spectrum of compound 5a exhibited two one-proton singlets at 5.50 (CH benzyl) and  5.60
(OH) ppm. The mass spectrum of compound 5b showed the molecular ion at m/z 584.
Formation of compound 5 could be explained by addition of two molecules of compound 1 to
compound 2 to form the intermediate 3 via retro Knoevenagel reaction followed by cyclization and elimination
of hydrogen cyanide. This reaction represents an interesting method for the construction and functionalization of
the 1-benzofuran ring systems. In addition, this method has the advantages of ready accessibility of the reagents,
good yields, and experimental simplicity.
In view of the above findings and in connection with the present work aiming to explore the synthetic
importance of enaminones, we studied the conversion of compound 2a into some new substituted furan
derivatives.
_______
* Deceased.
** To whom correspondence should be addressed, e-mail: mamegs@mans.edu.eg.
1 Department of Chemistry, Faculty of Science, University of Mansoura, Mansoura, Egypt.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 27-32, January, 2011. Original
article received March 31, 2010, in revised form October 26, 2010.
0009-3122/11/4701-0017©2011 Springer Science+Business Media, Inc.
17

Scheme 1
O
CN
CN
O
OR
+
Ar
NHPh
O
2a,b
1a–c
O
CN
H
O
O
1-propanol
piperidine
N
OR
NC
:
OR
NC
NC
OH
Ar
N
NHPh
O
O
NC
Ar
Ph
Ar
3a–c
– HCN
O
O
OR
CN
Ar
OR
Ph
H2N
O
H2N
NC
NHPh
N
O
NC
O
OH
Ar
Ar
4
5a–c
2 a R = Et, b R = Me; 3,5 a R = Et, Ar = Ph, b R = Me, Ar = p-ClC6H4,
c R = Me, Ar = p-BrC6H4
In the present work, the heterocyclic enaminone 2a has been condensed with aromatic amine 6 in
refluxing xylene to give compound 7, which we could not convert into compound 8 when treated with
formaldehyde (Scheme 2). The product 7 was characterized by analytical and spectral data (cf. Experimental).
Scheme 2
O
O
O
Me
O
O
O
NHC H -Me-
OEt
p
6
4
C H Me-
p
6
4
N
CH2O
+
NHPh
NHPh
O
xylene
O
N
O
Ph
NH2
2a
8
7
6
Treatment of compound 2a with the Vilsmeier reagent (Me2NCHO + POCl3) in tetrachloroethylene at
room temperature afforded the aldehyde 9 (Scheme 3). The structure of 9 was supported by its mass spectrum,
which showed the molecular ion at m/z 293.
18

Scheme 3
EtO2C
O
EtO2C
Cl
POCl3, TCE
Me2NCHO
PhHN
PhHN
CHO
O
O
9
2a
In view of the considerable chemical reactivity of ß-halo ketones, the authors felt it would be valuable to
investigate the reaction of the aldehyde 9 with hydrazines as a possible route to the furo[3,2-c]pyrazoles.
However, the treatment of compound 9 with hydrazine in a 1:1 molar ratio in absolute ethanol afforded the
corresponding hydrazone 10 instead of the expected product 11. On the other hand, the treatment of compound 9
with hydrazine in acetic acid afforded the azine 12 (Scheme 4). The structure 10 assigned to the product is based
on analytical and spectral data.
Several nucleophilic condensation reactions of compound 9 were also studied: this compound reacted
with malononitrile and with compound 2a to give furan derivatives 13 and 14, respectively (Scheme 4). The
structures assigned to the products are based on their analytical and spectral data. The mass spectrum of
compound 14 showed the molecular ion at m/z 522 (cf. Experimental).
Scheme 4
EtO2C
Cl
Cl
CO2Et
N
N
PhHN
NHPh
O
O
12
EtO2C
Cl
H
EtO2C
N
N
N
N2H4
AcOH
NH2
PhHN
O
PhHN
O
10
11
N2H4
EtOH
9
2a
CH2(CN)2
EtOH/piperidine
EtOH/piperidine
EtO2C
Cl
O
EtO2C
Cl
CO2Et
CN
PhHN
PhHN
CN
NHPh
O
O
O
14
13
EXPERIMENTAL
Melting points (uncorrected) were taken on a Fisher electric melting point apparatus. Elemental analyses
were carried out in the Microanalytical Unit, Faculty of Science, Mansoura and Cairo Universities.
19

1
Infrared spectra (pellets, KBr) were recorded on a SP-2000 Pye-Unicam spectrometer. H NMR spectra were
obtained with Varian-Gemini (200 MHz) and Brucker (250 MHz) spectrometers, internal standard TMS. Mass
spectra (EI) were recorded on a GCMS QP1000EX Shimadzu mass spectrometer (EI, 70 eV). The purity of the
synthesized compounds were tested by TLC using Merck TLC aluminum sheets, Cellulose F254, layer thickness
0.10 mm (ethyl acetate–ether, 9:1 as eluent), and no by-products were noticed in all cases.
Synthesis of Alkyl 5-Amino-7-aryl-2-{[aryl(hydroxy)methyl](phenyl)amino}-4,6-dicyano-1-benzo-
furan-3-carboxylates 5a-c. A mixture of compound 2a or 2b (0.003 mol) and the appropriate aryl-
idenemalononitrile 1a-c (0.006 mol) in 1-propanol (30 ml) and piperidine (0.1 ml) was refluxed for 8 h. The
solid products that precipitated after cooling were filtered off and crystallized from ethanol.
Ethyl 5-Amino-2-{[hydroxy(phenyl)methyl](phenyl)amino}-7-phenyl-4,6-dicyano-1-benzofuran-
3-carboxylate (5a) obtained as yellow crystals. Yield 83%; mp 205–207°C. IR spectrum, , cm–1: 3399 (OH),
3337, 3238 (NH2), 2198 (CN), 1660 (C=O ester). 1H NMR spectrum (200 MHz, CDCl3), , ppm (J, Hz): 1.25
(3H, t, J = 7.0, CH3 ester); 4.15 (2H, q, J = 7.0, CH2 ester); 5.05 (2H, s, NH2); 5.50 (1H, s, CH benzyl); 5.6 (1H,
s, OH); 7.19-7.45 (15H, m, H Ar). Found, %: C 72.51; H 4.71; N 10.82. C32H24N4O4. Calculated, %: C 72.72;
H 4.58; N 10.60.
Methyl 5-Amino-7-(p-chlorophenyl)-2-{[p-chlorophenyl(hydroxy)methyl](phenyl)amino}-4,6-dicyano-
1-benzofuran-3-carboxylate (5b) obtained as brown crystals. Yield 63%; mp 278-280°C (decomp.). IR
spectrum, , cm–1: 3407 (OH), 3339, 3234 (NH2), 2202 (CN), 1665 (C=O ester). Mass spectrum, m/z (I, %): 584
[M]+ (30), 553 [M-OMe]+ (34), 526 [M+H-(CO2Me)]+ (2), 442 [553-C6H4Cl]+ (6), 330 [553-C6H4Cl]+ (7), 93
(100). Found, %: C 63.61; H 3.32; N 9.51. C31H20Cl2N4O4. Calculated, %: C 63.82; H 3.46; N 9.60.
Methyl 5-Amino-7-(p-bromophenyl)-2-{[p-bromophenyl(hydroxy)methyl](phenyl)amino}-4,6-di-
cyano-1-benzofuran-3-carboxylate (5c) obtained as yellow crystals. Yield 60%; mp 288-290°C (decomp.). IR
spectrum, , cm–1: 3395 (OH), 3310, 3210 (NH2), 2198 (CN), 1670 (C=O ester). Mass spectrum, m/z (I, %): 674 [M]+
(17.1), 643 [M-OMe]+ (5.1), 485 [643-(C6H4Br+2H)]+ (5.8), 93 (100). Found, %: C 55.21; H 3.12; N 8.11.
C31H20Br2N4O4. Calculated, %: C 55.38; H 2.99; N 8.33.
4-Oxo-2-phenylamino-N-(p-tolyl)-4,5-dihydrofuran-3-carboxamide (7). A mixture of compound 2a
(0.003 mol) and p-toluidine 6 (0.003 mol) in xylene (15 ml) was refluxed for 6 h. The solid product obtained
after concentration and cooling was filtered off and crystallized from ethanol to give compound 7 as yellow
crystals. Yield 59%; mp 218-220°C. IR spectrum, , cm–1: 3300 (NH), 1638 (C=O ketone), 1561 (C=O amide).
Mass spectrum, m/z (I, %): 308 [M]+ (24), 202 [M-C7H8N]+ (29), 174 [202-CO]+ (4), 107 [C7H8N+H]+ (100), 92
[C7H8N+H-Me]+ (2), 77 [92-NH]+ (20). Found, %: C 70.25; H 5.38; N 9.25. C18H16N2O2. Calculated, %:
C 70.12; H 5.23; N 9.09.
Ethyl 4-Chloro-5-formyl-2-(phenylamino)furan-3-carboxylate (9). A cold solution of POCl3 (10 ml)
in tetrachloroethylene (TCE) (10 ml) and 3.56 ml DMF in TCE (40 ml) was added dropwise to a solution of
compound 2a (4.37 g) in TCE (40 ml). The reaction mixture was stirred for 16 h at room temperature. The solid
product that separated after neutralization with NaOH solution and extraction with CHCl3 was crystallized from
ethanol to give yellow crystals. Yield 70%; mp 129-131°C. IR spectrum, , cm–1: 3261 (NH), 1680 (C=O ester),
1653 (C=O aldehyde). Mass spectrum, m/z (I, %): 293 [M]+ (25), 195 (50), 130 (100). Found, %: C 57.31;
H 4.23; N 4.85. C14H12ClNO4. Calculated, %: C 57.25; H 4.12; N 4.77.
Ethyl 4-Chloro-5-(hydrazinylidenemethyl)-2-(phenylamino)furan-3-carboxylate (10). A mixture of
compound 9 (0.003 mol) and hydrazine hydrate (0.003 mol) in absolute ethanol (25 ml) was refluxed for 5 h.
The solid products that precipitated after cooling were filtered off and crystallized from the proper solvent to give
the hydrazone 10 as yellow crystals from ethanol. Yield 82%; mp 125-127°C. IR spectrum, , cm–1: 3349
(NH2 hydrazone), 3289 (NH), 1669 (C=O ester), 1639 (CN). Mass spectrum, m/z (I, %): 307 [M]+ (22), 262
[M-OEt]+ (3), 234 [M-CO2Et]+ (4), 142 [M-(C6H5NH+COOEt)]+ (9), 92 [C6H5NH]+ (7), 77 [C6H5]+ (100).
Found, %: C 54.73; H 4.73; N 13.75. C14H14ClN3O3. Calculated, %: C 54.64; H 4.59; N 13.66.
20

Diethyl 5,5'-(Hydrazine-1,2-diylidenedimethanylylidene)bis[4-chloro-2-(phenylamino)-furan-3-carboxy-
late] (12). A mixture of compound 9 (0.003 mol) and hydrazine hydrate (0.003 mol) in acetic acid (20 ml) was
refluxed for 6 h. The solid product that precipitated after cooling was filtered off and recrystallized from acetic
acid to give golden-yellow crystals. Yield 37%; mp 227-229°C. IR spectrum, , cm–1: 3293 (NH phenylamino),
1671 (C=O ester), 1621 (CN). Mass spectrum, m/z (I, %): 584 [M]+ (30), 308 [M+2H-C14H12NO3Cl]+ (23), 77
[C6H5]+ (100). Found, %: C 57.82; H 7.31; N 9.51. C28H24Cl2N4O6. Calculated, %: C 57.64; H 4.15; N 9.60.
Ethyl 4-Chloro-5-(2,2-dicyanovinyl)-2-(phenylamino)furan-3-carboxylate (13). A mixture of
compound 9 (0.003 mol) and malononitrile (0.003 mol) in absolute ethanol (25 ml) and piperidine (0.1 ml) was
refluxed for 6 h. The solid product that precipitated out after cooling was filtered off and recrystallized from
ethanol to give yellow crystals. Yield 63%; mp 139-141°C. IR spectrum, , cm–1: 3324 (NH phenylamino), 2192
1
(CN), 1715 (C=O ester), 1633 (C=C). H NMR spectrum (250 MHz, DMSO-d6), , ppm (J, Hz): 1.37 (3H, t,
J = 7.0, CH3 ester); 4.35 (2H, q, J = 7.0, CH2 ester); 7.25–7.55 (6H, m, H Ar+vinyl); 10.1 (1H, s, NH). Found,
%: C 59.86; H 3.61; N 12.41. C17H12ClN3O3. Calculated, %: C 59.73; H 3.54; N 12.29.
Ethyl 4-Chloro-5-[(4-ethoxycarbonyl-3-oxo-5-(phenylamino)furan-2(3H)-ylidene]methyl-2-(phenyl-
amino)furan-3-carboxylate (14). A mixture of compound 9 (0.003 mol) and compound 2a (0.003 mol) in
absolute ethanol (30 ml) and piperidine (0.1 ml) was refluxed for 6 h. The reaction mixture was cooled, poured
in water, and acidified with diluted HCl, 1:1. The precipitated material was filtered off and recrystallized from
ethanol to give brown crystals. Yield 58%; mp 219-221°C. IR spectrum, , cm–1: 3300 (NH phenylamino), 1664
(C=O ester), 1619 (CH=C). Mass spectrum, m/z (I, %): 523 [M+1]+ (2), 522 [M]+ (28), 487 [M- HCl]+, probably
the fused pyrylium ion (93), 395 [M-HCl-(2EtO+2H)]+ (55), 77 [C6H5]+ (100). Found, %: C 62.13; H 4.51; N 5.43.
C27H23ClN2O7. Calculated, %: C 62.01; H 4.43; N 5.36.
REFERENCES
1.
2.
3.
4.
The Merck Index of Chemicals and Drugs, 12th Ed., Merck and Co., Inc., 1996, p. 406.
The Merck Index of Chemicals and Drugs, 12th Ed., Merck and Co., Inc., 1996, p. 409.
S. Prabhakar, B. R. Pai, and V. N. Ramachandran, Indian J. Chem., 8, 857 (1970).
S. C. Kuo, S. C. Huang, L. J. Huang, E. H. Cheng, T. S. Ping, C. H. Wu, K. Ishii, and H. Nakamura,
J. Heterocycl. Chem., 28, 955 (1991).
5.
6.
7.
8.
9.
10.
11.
12.
R. A. Mack, St. G. Vassil, S. C. Wu Edwin, and R. M. James, J. Org. Chem., 58, 6158 (1991).
M. Hammouda, M. M. Mashaly, and A. A. Fadda, Arch. Pharm. Res., 18, 213 (1995).
M. Hammouda, M. M. Mashaly, and E. M. Afsah, Pharmazie, 49, 365 (1994).
M. M. Mashaly and M. Hammouda, Z. Naturforsch., 54b, 1205 (1999).
M. Hammouda, A. S. El-Ahl, Y. M. El-Toukhee, and M. A. Metwally, J. Chem. Res. (S), 89 (2002).
A. W. Faull and R. Hull, J. Chem. Soc., Perkin Trans. 1, 1078 (1981).
L. Capuano and W. Fisher, Chem. Ber., 109, 212 (1976).
R. Gr. Redkin, L. A. Shemchuk, V. P. Chernykh, O. V. Shishkin, and S. V. Shishkina, Tetrahedron, 63,
11444 (2007).
13.
14.
15.
16.
X. Z. Lian, Y. Huang, Y. Q. Li, and W. J. Zheng, Monatsh. Chem., 139, 129 (2008).
M. Xia, Q. Chen, and Y. Lu, Synth. Commun., 35, 1381 (2005).
D. Shi, J. Mou, Q. Zhuang, L. Niu, N. Wu, and X. Wang, Synth. Commun., 34, 4557 (2004).
B. P. V. Lingaiah, G. V. Reddy, T. Yakaiah, B. Narsaiah, S. N. Reddy, R. Yadla, and P. S. Rao, Synth.
Commun., 34, 4431 (2004).
21