Acid-mediated cyclization of 3-benzoyl-2-cyanobutyronitrile to 2-amino-4-methyl-5-phenylfuran-3-carbonitrile

Article abstract of DOI:10.3987/COM-03-S(P)13

Cyclization of 3-benzoyl-2-cyanobutyronitrile to 2-amino-4-methyl-5-phenylfuran-3-carbonitrile was effected under acidic conditions, rather than the basic conditions previously reported. Since treatment with trifluoroacetic acid (TFA) at room temperature is very mild, 2-amino-4-methyl-5-phenylfuran-3-carbonitriles containing various functional groups can be accessed via this route.

Full text of DOI:10.3987/COM-03-S(P)13

HETEROCYCLES, Vol. 62, 2004, pp. 127 - 130
Received, 26th June, 2003, Accepted, 8th August, 2003, Published online, 14th October, 2003
ACID-MEDIATED
BUTYRONITRILE
CARBONITRILE
CYCLIZATION
OF
3-BENZOYL-2-CYANO-
TO 2-AMINO-4-METHYL-5-PHENYLFURAN-3-
Susumu Watanuki,* Shuichi Sakamoto, Hironori Harada, Kazumi Kikuchi,
Takahiro Kuramochi, Ken-ichi Kawaguchi, Toshio Okazaki, and Shin-ichi
Tsukamoto
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21
Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan
Abstract - Cyclization of 3-benzoyl-2-cyanobutyronitrile to 2-amino-4-methyl-
5-phenylfuran-3-carbonitrile was effected under acidic conditions, rather than the
basic conditions previously reported. Since treatment with trifluoroacetic acid
(TFA) at room temperature is very mild, 2-amino-4-methyl-5-phenylfuran-3-
carbonitriles containing various functional groups can be accessed via this route.
Substituted 2-aminofuran-3-carbonitriles are useful intermediates in the synthesis of furo[2,3-b]-
pyrimidines and furo[2,3-b]pyridines.1
There have been many reports on the synthesis of
2-aminofuran-3-carbonitriles,2 most of them involving the cyclization of phenacylmalononitrile, mediated
by base. Synthesis of functionalized 2-aminofuran-3-carbonitriles, according to a previously reported
procedure (Et2NH, DMF),3 was attempted without success. Various conditions were investigated to
promote the required cyclization and it was discovered that cyclization could be accomplished by
treatment with acid.
In this communication, an improved method for the synthesis of
2-amino-4-methyl-5-phenylfuran-3-carbonitrile (2a) is reported and the scope of this reaction is
discussed.
In order to promote the cyclization, activation of the nucleophilic species (ketone) or electrophilic species
(nitrile) is required (Scheme 1). Most of the previously reported cyclizations were induced by activation
of the ketone, which was converted to enol form under basic conditions (A). However the electrophilic
cyano group was deactivated by deprotonation because the acidity of the α-proton of malononitrile
moiety was higher than that of the carbonyl function. This deactivation obstructed the desired
cyclization. It was assumed that activation of nitrile could be accomplished by protonation of the
nitrogen in acidic media (C), and the carbonyl oxygen could then attack the highly activated nitrile group
(D).
Dedicated to Professor L. A. Paquette on the occasion of his 70th birthday.
Corresponding author. e-mail: watanuki.susumu@yamanouchi.co.jp

Scheme 1
O
CN
CN
O
N
Base-mediated
cyclization
+H+
-H+
Me
Me
CN
-H+
A
O
CN
B
O
NH2
CN
CN
NH+
Me
1a
+H+
Me
O
O+
2a
NH
CN
Acid-mediated
cyclization
CN
Me
Me
C
D
3-Benzoyl-2-cyanobutyronitrile (1a) was treated with various acids (Table 1). It has been previously
reported that when counter anions were highly nucleophilic, intermolecular attack of the counter anion on
the nitrile was the predominant pathway to provide pyrrole derivatives (X=Cl, Br).4 In the case of
trifluoroacetic acid (TFA) and trifluoromethanesulfonic acid (TfOH), the desired compound (2a) was
obtained in 77% and 52% yields respectively. Since the trifluoroacetate anion and trifluoromethane
sulfonate anion are very weak nucleophiles, intramolecular attack by the carbonyl oxygen proceeded.
When 1a was treated with H2SO4 and AcOH respectively, the desired compound (2a) was not formed.
Among the conditions examined, TFA gave the optimal results.
Scheme 2
H
O
CN
CN
N
O
conditions
X
NH2
+
Me
Me
3a
CN
Me
CN
1a
2a
Table 1 Cyclization of 1aa)
Yield
conditions
2a
3a
HCl, EtOH
HBr, AcOH
49% (X=Cl)
41% (X=Br)
TFA
77%
52%
b)
CF3SO3H
b)
Decomposed
No reaction
H2SO4
c)
AcOH
a) All reactions were carried out at room temperature
unless otherwise noted.
b) Reactions were carried out at 0 ℃
c) up to 110 ℃
In order to investigate the scope of this reaction, the effect of substituents on the aromatic ring was
examined (Table 2).5 Whether electron withdrawing groups or electron donating groups were attached
to the phenyl ring, the reactions proceeded at room temperature. Reaction time was dependent on the
substituent on the phenyl ring (completion of the reaction was monitored by TLC or HPLC). Assuming
that the reaction rate can be estimated by the reaction time, the order of reaction rate was
OMe=OBn>H>Cl>CF3>CO2Me>SO2Me. These results can be explained by examining the

nucleophilicity of the carbonyl oxygen. Electron donating groups increased the electron density of the
carbonyl oxygen, and the reaction rate increased. In contrast, electron withdrawing groups decreased
the reaction rate. In addition, a greater decrease in reaction rate was observed with electron withdrawing
groups at the 4-position on the phenyl ring, than at the 3-position (Table 2 runs 5 and 6, 7 and 8).
Therefore, these results indicate that cyclization occurs with the keto form, as opposed to the enol form
(Scheme 1, C).
Scheme 3
O
CN
CN
O
TFA
NH2
CN
R
R
Me
Me
1
2
Table 2 Effect of substituentsa)
Yield of 2
run
R
60%
70%
45%
47%
1
2
2-OMe
2-OBn
4-Cl
3
4
5
6
7
8
4-CF3
47%
3-CO2Me
4-CO2Me
37%
49%
26%
b)
c)
3-SO2Me
4-SO2Me
a) All reactions were carried out at room temperature
unless otherwise noted.
b) Reaction was carried out at room temperature
for 24 h then at 50 ℃ for 4 h.
c) Starting material was recovered at 33% yield.
To expand the synthetic utility of this reaction, other substituents at the 4-position of furan ring were
examined (Table 3). The reactions of compounds containing ethyl, isopropyl and phenyl groups were
investigated in a similar manner, and furan (2), which contains an acetate group in the 4-position, was
synthesized at 66% yield.
Scheme 4
O
CN
CN
O
TFA
NH2
CN
Table 3 Synthesis of 2 having various substituents at 4-position a)
R
R
1
2
R
Yield of 2
77%
82%
51%
Me
Et
i-Pr
65%
66%
Ph
CH2CO2Me
a) All reactions were carried out at room temperature.

In conclusion, an improved synthetic route for the synthesis of 2-aminofuran-3-carbonitriles was
identified. Acid-mediated cyclization is promoted using TFA and proceeds under mild reaction
conditions, which provides access to many functionalized 2-aminofuran-3-carbonitriles.
General Procedure; 3-Benzoyl-2-cyanobutyronitrile (1a; 2.0 g, 10.1 mmol) was cooled in an ice-water
bath while TFA (10 mL) was carefully added. The solution was stirred at rt for 1 h. Concentration,
drying followed by crystallization (AcOEt-hexane) of the resulting solid afforded 1.54 g (77% yield) of
2-amino-4-methyl-5-phenylfuran-3-carbonitrile (2a).
REFERENCES AND NOTE
1. (a) T. I. Temnikova, Y. A. Sharanin, and V. S. Karavan, Org. Khim., 1967, 3, 681. (b) 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. C. Lockhart and J. W. Sowell, J. Heterocycl. Chem., 1996, 33, 659. (d) F. M.
Abdelrazek and A. M. Salah, Egypt. J. Chem., 1997, 40, 105.
2. (a) A. O. Abderhamid, A. M. Negm, and I. M. Abbas, J. Prakt. Chem., 1989, 331, S.31. (b) J. G.
Jun, Bull. Korean Chem. Soc., 1996, 17, 676. (c) X. Feng, J. C. Lancelot, H. Prunier, and S. Rault, J.
Heterocycl. Chem., 1996, 33, 2007.
3. X. Feng, J. C. Lancelot, A. C. Gillard, H. Landelle, and S. Rault, J. Heterocycl. Chem., 1998, 35,
1313.
4. L. H. Foley, Tetrahedron Lett., 1994, 35, 5989.
5. Compound (1) having various functional groups was prepared as shown in the following scheme
(Scheme 5). Bromination (Br2, Et2O) of corresponding ketone followed by substitution with
malononitrile gave the compound (1).
Scheme 5
O
O
1
CN
CN
O
Br
R2
NC
CN
Br2
Et2O
R1
R1
R1
R2
NaH or KOBu-t
R2
THF
4
5