One-pot synthesis of substituted 2-amino-3-furonitriles

Article abstract of DOI:10.3184/030823408X356314

Solvent-free reaction of substituted a-haloketones with malononitrile in the presence of diethylamine provides an efficient one-pot synthesis of 2-amino-5-aryl (alkyl)-3-furonitriles in high yield.

Full text of DOI:10.3184/030823408X356314

564 RESEARCH PAPER
OCTOBER, 564–565
JOURNAL OF CHEMICAL RESEARCH 2008
One-pot synthesis of substituted 2-amino-3-furonitriles
Mehdi Bakavoli*, Mohammad Rahimizadeh and Zinat Gordi
Department of Chemistry, Ferdowsi University of Mashhad, Mashhad 91775-1436, Iran
Solvent-free reaction of substituted a-haloketones with malononitrile in the presence of diethylamine provides an
efficient one-pot synthesis of 2-amino-5-aryl (alkyl)-3-furonitriles in high yield.
Keywords: 2-aminofuronitrile, furo[2,3-d]pyrimidine, heterocyclisation, phenacyl bromides
Substituted 2-amino-3-furonitriles are useful intermediates
in the synthesis of furo[2,3-b]pyridines and furo[2,3-d]
pyrimidines.1-7 There have been many reports on the synthesis
of polyheterocyclic compounds from these precursors which
showed interesting biological activities.8-13 In the most of
the procedures,8,9,14 a phenacylmalononitrile derivative was
prepared from a phenacyl bromide, which then cyclised in the
presence of an acid or a base. Acid-catalysed cyclisation of
this intermediate gave predominantly a pyrrole derivative.14,15
Another problem in the synthesis of furan derivatives, is
a facile dimerisation of product by way of a Diels–Alder
cycloaddition.16,17 In pursuit of our work on the synthesis of
polyheterocyclic systems,18-22 we report a convenient one-
pot synthesis of 2-amino-5-aryl (alkyl)-3-furonitriles (3a–h)
under solvent-free conditions (Scheme 1).
and malononitrile in the presence of diethylamine furnished
exclusively the 2-amino-5-aryl (alkyl)-3-furonitriles (3a–h) as
shown in Scheme 1 and Table 1. In these reactions only furans
were obtained in high yields without any byproduct formation
such as pyrrole or furan-dimer. In the presence of other bases
such as pyridine and triethylamine, the conversion decreased
and a mixture of products was obtained.
The structures of new compounds were confirmed by
spectral data. For example, the IR spectrum of 3f was devoid
of the stretching vibration bands at 1700 cm-1 for carbonyl
absorption of the phenacyl bromide but instead showed new
absorption bands at 3400, 3320 and 2200 cm-1 for amine and
nitrile groups, respectively. The 1H NMR spectra in d6-DMSO
showed a broad singlet at 8.40 ppm due to NH2 group as well
as characteristic signals corresponding to m-nitro-aryl group
protons. The furan proton gave a singlet at 6.95 ppm. The
Mass spectrum of the compound showed the molecular ion
peak at m/z 229 corresponding to the (M+). This compound
gave a satisfactory elemental analysis data.
In conclusion, we have developed a facile method for the
one pot synthesis of 2-amino-5-aryl (alkyl)-3-furonitriles
through base-catalysed cyclocondensation of phenacyl
bromide derivatives and malononitrile. Compared to the
current syntheses of 2-amino-furan-3-carbonitriles, we have
developed a simple and highly efficient method for one-pot
synthesis of the title compounds under solvent-free conditions.
The efficiency of the present work is apparent from high yields
with the lack of side products.
Results and discussion
Reaction of phenacyl bromide (1a) and malononitrile in the
presence of potassium tert-butoxide in THF gave exclusively
the phenacylmalononitrile (4a) in 90% yield. Our attempts
to convert the latter to furan (3a) under different conditions
failed. In the case of trifluoroacetic acid (TFA) a mixture of
furan and pyrrole derivatives was obtained. Heteropolyacid
treatment in different solvents, reaction temperatures and long
reaction times were also unsuccessful. We were then tried
to find a straightforward procedure to prepare 2-amino-3-
furonitriles from phenacyl bromide derivatives. Interestingly,
grinding a mixture of phenacyl bromide derivatives (1a–h)
O
R2
R1
CN
Et2NH / SiO2
CN
CN
R2
+
R1
NH2
Solvent-free
15 min grinding
O
X
1a–h
3a–h
2
t-BuOK, THF
reflux, 4h, 90%
CN
X
CN
NH2
O
CN
CN
Cat.
+
Ph
R1
Ph
N
H
O
R2
5a
3a
4a) R2=H, R1=Ph
Cat.:
TFA, RT, 1 h
60 %
40 %
H3PW12O40, EtOH, reflux, 5 h
H3PW12O40, Solvent-free, 30 min
H3PW12O40, MW,10 min
No reaction
No reaction
No reaction
Scheme 1
* Correspondent. E-Mail: mbakavoli@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2008 565
Table 1 Synthesis of 2-amino-3-furonitriles under solvent-free conditionsa
Entry
a-Haloketone
2-Amino-3-furonitrile
Isolated yield/%
M.p./°Cb
1
3
Found
Lit.ref
20023
O
CN
a
80
200–201
Br
NH2
CN
O
O
b
c
75
70
213–215
218–220
214–21524
220–22224
H3CO
H3C
Br
Br
NH2
CN
NH2
O
H3CO
H3C
O
O
CN
O
O
d
85
224–225
24–22624
Cl
Br
Br
Br
NH2
CN
O
Cl
e
f
90
65
229–230
200–201
228–22924
–
NH2
CN
NH2
O
Br
O
O
Br
O2N
O2N
O
H3C
CN
g
h
70
155–157
15823
Br
NH2
CN
O
O
Cl
60
154–156
156–15825
H3C
NH2
O
aThe products were characterised by comparison of their IR and 1H NMR spectroscopic data and their melting points are compared
with reported values.
bIn all cases the products melt with decomposition.
3
M.M. Ali, Y.A. Zahran, Y.A. Ammar, A.T. Mohamed and A.T. Seleim,
Indian J. Heterocycl. Chem., 1995, 126, 191.
C.C. Lockhart and J.W. Sowell, J. Heterocycl. Chem., 1996, 33, 659.
J.I. Pyo, E.J. Hwang, C.S. Cheong, S.-H. Lee, S.W. Lee, I.T. Kim and
S.H. Lee, Synth. Meth., 2005, 155, 461.
M.M.H. Bhuiyan, K.M.M. Rahman, M.K. Hossain, M.A. Rahim and
M.I. Hossain, Croat. Chem. Acta, 2005, 78, 633.
R.M. Shaker, Arkivoc, 2006, part (xiv), 68.
Y. Miyazaki, S. Matsunaga, J. Tang, Y. Maeda, M. Nakano, R.J. Philippe,
M. Shibahara, W. Liu, H. Sato, L. Wang and R.T. Nolte, Bioorg. Med.
Chem. Lett., 2005, 15, 2203.
Y. Maeda, M. Nakano, H. Sato, Y. Miyazaki, S.L. Schweiker, J.L. Smith
and A.T. Truesdale, Bioorg. Med. Chem. Lett., 2004, 14, 3907.
Experimental
The melting points were recorded on an Electrothermal type 9100
melting point apparatus. The IR spectra were obtained on a 4300
Shimadzu Spectrometer. The H NMR (100 MHz) spectra were
recorded on a Bruker AC 100 spectrometer. The mass spectra were
scanned on a Varian Mat CH-7 instrument at 70 eV. Elemental analyses
was obtained on a Thermo Finnigan Flash EA microanalyser.
4
5
1
6
7
8
General procedure for the synthesis of 2-amino-5-aryl(alkyl)-3-
furonitriles (3a–h)
9
A mixture of phenacyl bromide derivatives (1a–h) (2 mmol),
malononitrile (0.13 g, 2 mmol), SiO2 (1.0 g) and diethylamine (0.44 g,
6 mmol) was ground in a mortar for 15 min. After the completion
of the reaction (monitored by TLC CHCl3:CH3OH 9:1), the reaction
mixture was washed with chloroform (30 ml). The organic layer was
washed with water (2 ¥ 30 ml), dried over MgSO4 and evaporated.
The crude product was recrystallised from ethanol to give
compounds (3a–h) in 60–90% yields. The 2-amino-5-aryl(alkyl)-
3-furonitriles (3a–e and 3g–h) prepared are known compounds and
were characterised by comparison of their physical and spectral data
with those reported in the literature.8-14, 23-25
2-Amino-5-(3-nitrophenyl)-3-furonitrile (3f): Compound 3f was
obtained in 65% yield; yellow solid; m.p. 200–201°C; IR (KBr,
νmax/cm-1): 3400 (NH), 3320 (NH), 2200 (CN), 1650 (NH2),
1530 (NO2), 1350 (NO2). 1H NMR (DMSO-d6, 100 MHz) δ: 6.95 (s,
1H, Furan H), 7.55 (t, 1H, J = 8 Hz, ArH–H5), 8.05 (td, 1H, J1 = 8 Hz,
J2 = 1.5 Hz, ArH–H6), 8.15 (td, 1H, J1 = 8 Hz, J2 = 1.5 Hz, ArH–H4),
8.25 (t, 1H, J = 1.5 Hz, ArH–H2), 8.40 (br s, 2H, NH2). MS: m/z 229
(M+, 45), 194 (35), 183 (25), 125 (55), 107 (63), 93 (71), 77 (100), 65
(45). Found: C, 57.42; H, 2.97; N, 18.64. Calcd for C11H7N3O3 (229):
C, 57.65; H, 3.08; N, 18.33%.
10 Y. Miyazaki, J. Tang, Y. Maeda, M. Nakano, L. Wang, R.T. Nolte,
H. Sato, M. Sugai, Y. Okamoto, A.T. Truesdale, D.F. Hassler, E.N. Nartey,
D.R. Patrick, M.L. Ho and K. Ozawa, Bioorg. Med. Chem. Lett., 2007,
17, 1773.
11 E.F. DiMauro, J. Newcomb, J.J. Nunes, J.E. Bemis, C. Boucher,
J.L. Buchanan, W.H. Buckner, A. Cheng, T. Faust, F. Hsieh, X. Huang,
J.H. Lee, T.L. Marshall, M.W. Martin, D.C. McGowan, S. Schneider, S.M.
Turci, R.D. White and X. Zhu, Bioorg. Med. Chem. Lett., 2007, 17, 2305.
12 S.Y. Kim, D.J. Kim, B.S. Yang and K.H. Yoo, Bull. Kor. Chem. Soc.,
2007, 28, 1114.
13 E.C. Taylor, H.H. Patel and J.-G. Jun, J. Org. Chem., 1995, 60, 6684.
14 S. Watanuki, S. Sakamoto, H. Harada, K. Kikuchi, T. Kuramochi,
K.-I. Kawaguchi, T. Okazaki and S.-I. Tsukamoto, Heterocycles, 2004,
62, 127.
15 L.H. Foley, Tetrahedron Lett., 1994, 35, 5989.
16 J.L. Isidor, M.S. Brookhart and R.L. McKee, J. Org. Chem., 1973, 38, 612.
17 J.-G. Jun, Bull. Korean Chem. Soc., 1996, 17, 676.
18 M. Bakavoli, F.A. Sani, A. Davoodnia, M. Roshani and F. Pirouzi,
Heterocyclic Commun., 2007, 13, 371.
19 M. Bakavoli, B. Reihani, M. Rahimizadeh and M. Nikpour, Phosphorus
Sulfur Silicon, 2006, 181, 99.
20 A. Davoodnia, M. Bakavoli, A. Vahedinia, M. Rahimizadeh and
M. Roshani, Heterocycles, 2006, 68, 801.
21 M.M. Heravi, M. Bakherad, M. Rahimizadeh, M. Bakavoli and
M. Ghassemzadeh, Heterocyclic Commun., 2004, 10, 335.
22 A. Davoodnia, M.M. Heravi, E. Golshani and M. Bakavoli, J. Chem. Res.,
2007, 257.
Received 24 June 2008; accepted 11 August 2008
Paper 08/0016 doi: 10.3184/030823408X356314
Published online: 8 October 2008
References
23 X. Feng, J.-C. Lancelot, A.-C. Gillard, H. Landelle and S. Rault,
J. Heterocycl. Chem., 1998, 35, 1313.
1
T.I. Temnikova, Y.A. Sharanin and V.S. Karavan, Zh. Org. Khim., 1967,
24 V.S. Caravan, S.N. Semenova and A.K. Shchurinova, Zh. Org. Khim.,
1969, 5, 2161.
25 K. Gewald, Chem. Ber., 1966, 99, 1002.
3, 681.
2
K.R. Jyothikumari and K.N. Rajasekharan, J. Indian Chem. Soc., 1991,
68, 660.