Oxidative cyclization of 3-oxopropanenitriles with α,β-unsaturated amides by manganese(III) acetate. Regio- and stereoselective synthesis of 4-cyano-2,3-dihydrofuran-3-carboxamides

Article abstract of DOI:10.1016/j.tet.2007.04.088

4-Cyano-2,3-dihydrofuran-3-carboxamides were obtained from the oxidative cyclization of 3-oxopropanenitriles with unsaturated amides using manganese(III) acetate. Treatment of 3-oxopropanenitriles with (2E)-3-(5-methyl-2-furyl)acrylamide and (2E)-3-(2-thi

Full text of DOI:10.1016/j.tet.2007.04.088

Tetrahedron 63 (2007) 7229–7239
Oxidative cyclization of 3-oxopropanenitriles with
a,b-unsaturated amides by manganese(III) acetate.
Regio- and stereoselective synthesis of
4-cyano-2,3-dihydrofuran-3-carboxamides
a
a
E. Vildan Burgaz,a Mehmet Yılmaz,b, A. Tarık Pekel and Atilla Oktemer
¨
*
aDepartment of Chemistry, Faculty of Sciences, Ankara University, 06100 Tandogan, Ankara, Turkey
bDepartment of Chemistry, Faculty of Arts and Sciences, Kocaeli University, 41380 Umuttepe, Kocaeli, Turkey
Received 18 February 2007; revised 9 April 2007; accepted 26 April 2007
Available online 3 May 2007
Abstract—4-Cyano-2,3-dihydrofuran-3-carboxamides were obtained from the oxidative cyclization of 3-oxopropanenitriles with unsatu-
rated amides using manganese(III) acetate. Treatment of 3-oxopropanenitriles with (2E)-3-(5-methyl-2-furyl)acrylamide and (2E)-3-(2-
thienyl)acrylamide gave 2-(5-methyl-2-furyl) and 2-(2-thienyl) substituted 4-cyano-2,3-dihydrofuran-3-carboxamides in moderate yields,
respectively. However, (2E)-3-(2-furyl)acrylamide and (2E)-3-phenylacrylamide did not produce any product under the same conditions.
On the other hand, reaction of a dienamide such as (2E,4E)-5-phenylpenta-2,4-dienamide with 3-oxopropanenitriles gave diastereomeric
mixtures of 2-(2-vinylphenyl)-4-cyano-2,3-dihydrofuran-3-carboxamides. Mechanisms are proposed for the formation of all of these com-
pounds.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
diarylethylenes and their reaction mechanism have been
reported by Nishino et al.9 Previously, we have studied oxi-
dative cyclization of 3-oxopropanenitriles with conjugated
alkenes containing phenyl and 2-thienyl groups using man-
ganese(III) acetate.3o Recently, we have also reported the
synthesis of 4,5-dihydrofurans and naphthalene derivatives
including carboxamides due to the reaction of 1,3-di-
carbonyls with a,b-unsaturated amides such as acrylamide
and methacrylamide.3l
Dihydrofurans belong to an important class of compounds
which show a wide range of biological activities and form
the basic structure of many natural products.1 These com-
pounds can be produced by the reactions of diazo com-
pounds or iodonium ylides with alkenes via Rh(II)
catalysis.2 More commonly, they are produced from
reactions of active methylene compounds (1,3-dicarbonyl,
b-ketoester and 3-oxopropanenitrile) with alkenes by using
transition metal salts (e.g., Mn+3, Ce+4, Co+3, Cu+2). Among
these metal salts, manganese(III) acetate3 and cerium(IV)
ammonium nitrate4 have very important roles, and they allow
the formation of highly functionalized products such as
furans,3c–f,5 dihydrofurans,3g–p g-lactones,6 b-lactams7 and
natural products.3c,r,8
Up to now, reactions of a,b-unsaturated amides with 3-
oxopropanenitriles have not been studied. Here, we describe
the oxidative cyclizations of various 3-oxopropanenitriles
1a–h with a,b-unsaturated amides containing 2-thienyl, 2-
furyl, 2-(5-methylfuryl), phenyl and phenylvinyl groups by
using manganese(III) acetate. As a result of these reactions,
we have obtained 4-cyano-2,3-dihydrofurans containing
carboxamides.
Recently, we reported the synthesis of 3-trifluoroacetyl-4,5-
dihydrofurans and 3-(dihydrofuran-2(3H)-ylidene)-1,1,1-
trifluoroacetones by the treatment of trifluoromethyl-1,3-
dicarbonyl compounds with conjugated alkenes.3n The
oxidative cyclization of 3-oxopropanenitriles with 1,1-
2. Results and discussion
(2E)-3-(5-Methyl-2-furyl)acrylamide 2a, (2E)-3-(2-furyl)-
acrylamide 2b, (2E)-3-(2-thienyl)acrylamide 2c10 and
(2E,4E)-5-phenylpenta-2,4-dienamide 2e were obtained
from the reaction of ammonia with the acyl chloride (ob-
tained by the reaction of the carboxylic acids with SOCl2).
Keywords: Manganese(III) acetate; Oxidative cyclization; Radical addition;
2,3-Dihydrofuran; Carboxamide; 3-Oxopropanenitrile; Unsaturated amide.
* Corresponding author. Tel.: +90 262 3032058; fax: +90 262 3032003;
e-mail: mehmet.yilmaz@kou.edu.tr
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.088

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E. V. Burgaz et al. / Tetrahedron 63 (2007) 7229–7239
All 3-oxopropanenitriles (except 1d) were prepared by the
condensation of suitable esters with acetonitrile and NaH
in PhMe.11
H2NOC
H
R
O
Ph
O
Ar
CN
X
R = Me, X = O : 3a-g
R = H, X = S : 3h-m
H
COMe
H2NOC
The mechanism we propose for the oxidative cyclization of
a,b-unsaturated amides 2a–d with 3-oxopropanenitriles is
explained in Scheme 1. According to this mechanism, inter-
action of Mn(OAc)3 with the enol form of 3-oxopropane-
nitrile A gives a manganese(III)–enolate complex B. In
complex B, an a-carbon radical C is formed on 3-oxopro-
panenitrile while Mn+3 is reduced to Mn+2. This a-carbon
radical attacks the unsaturated amide, and compound D
can be formed following pathway i, or compound G can
be formed following pathway ii. Structure D is oxidized to
carbocation E by Mn(OAc)3 and intramolecular cyclization
of E forms 2,3-dihydrofuran-3-carboxamide F. Structure G
following the same two steps forms 2,3-dihydrofuran-2-
carboxamide H.
F
I
Figure 1.
(Table 1). Treatment of 3-phenyl-3-oxopropanenitrile 1a
with 2a gave the product 2,3-dihydrofuran 3a in 56%
yield. Additionally, 4-cyano-2,3-dihydrofuran-3-carboxamides
3b–d were obtained via the oxidative reaction of 2a with
derivatives of 1a such as 4-Me 1b, 4-MeO 1c and 4-Cl 1d
in 42, 64 and 55% yields, respectively. We have also
obtained 3e (53%) and 3f (49%) in moderate yields, respec-
tively, in the oxidative cyclization of 3-oxopropanenitriles
1e and 1f containing heterocyclic group with 2a. In addition,
the treatment of 4,4-dimethyl-3-oxopentanenitrile 1g
with 2a formed 2,3-dihydrofuran-3-carboxamide 3g in
1
Radical intermediate product in structure D is more stable
than G since it is conjugated with an aromatic group. Conse-
quently, we have obtained 2,3-dihydrofuran-3-carbox-
amides F regio- and stereoselectively, but the other product
G is not produced. These two compounds were differenti-
ated by the chemical shift values of the H-2 protons.
We had reported the chemical shift value of the H-2 proton
of 4-acetyl-5-phenyl-2,3-dihydrofuran-2-carboxamide I as
dH¼5.01 ppm (Fig. 1).3l However, the chemical shift values
for the H-2 protons and H-3 protons are 5.73–6.56 ppm and
3.86–4.32 ppm, respectively, in the 1H NMR spectra of
isolated compounds 3a–m. Thus, we concluded that these
compounds are 2,3-dihydrofuran-3-carboxamides F formed
via pathway i.
42% yield. The H NMR spectra of 2-(5-methyl-2-furyl)
substituted 4-cyano-2,3-dihydrofuran-3-carboxamides 3a–g
show that the 5-methylfuryl and carboxamide groups
are in trans position since the coupling constant between
H2 and H3 protons of these compounds Jtrans¼6.4–7.6 Hz.
It is reported that the coupling constant between these
protons in same structures are given as Jcis¼8–9 Hz, in
literature.12
Oxidative cyclizations of (2E)-3-(2-thienyl)acrylamide 2c
with 3-oxopropanenitriles produced 2-(2-thienyl) subs-
tituted 2,3-dihydrofuran-3-carboxamides 3h–m in moderate
yields similar to the ones of 2a (Table 2). We obtained 2,3-
dihydrofurans 3h (47%) and 3i (49%) in the reactions of
2c with 1a and 1c, respectively. The reaction of 1e with 2c
gave 4-cyano-2,5-di-2-thienyl-2,3-dihydrofuran-3-carbox-
amide 3j in 43% yield. Similarly, 3k (34%) and 3l (45%)
were produced as a result of radical cyclization of 3-oxopro-
panenitriles containing 2-furyl (1h) and 2-benzofuryl (1f)
groups with 2c, respectively. Coupling constant between
While no product was obtained in the oxidative cyclization
of 3-oxopropanenitriles with (2E)-3-(2-furyl)acrylamide
2b using manganese(III) acetate, the reaction of 1a–g
with (2E)-3-(5-methyl-2-furyl)acrylamide 2a formed 2,3-
dihydrofuran-3-carboxamides 3a–g in moderate yields
Mn+2
Mn+2
O
Mn+3
O
O
H2NOC
N
N
R
O
ii
C
C
N
R
R
C
R
CN
Ar
ii
B
C
Ar
Ar
i
H2NOC
G
H
CONH2
Mn(OAc)3
2a-d
i
OH
N
C
R
Mn+2
C
Mn+2
C
A (1a-h)
O
O
O
N
N
Ar
R
Mn(OAc)3
R
R
Ar = 5-Me-2-furyl : 2a
Ar = 2-Furyl : 2b
Ar = 2-Thienyl : 2c
Ar = Ph : 2d
H2NOC
Ar
CN
+
CONH2
CONH2
Ar
F (3a-m)
D
E
Scheme 1. Mechanism for formation of 2,3-dihydrofuran-3-carboxamides.

E. V. Burgaz et al. / Tetrahedron 63 (2007) 7229–7239
Table 1. Synthesis of 2-(5-methyl-2-furyl)-4-cyano-2,3-dihydrofuran-3-carboxamides 3a–g
7231
Entry
3-Oxopropanenitrile
a,b-Unsaturated amide
4-Cyano-2,3-dihydrofuran-3-carboxamide
Product and
yield,a %
O
O
O
O
O
CN
1
3a, 56
3b, 42
3c, 64
NH2
H2N
O
CN
1a
2a
O
O
O
CN
2
3
2a
CN
H2N
1b
O
OMe
O
O
O
CN
2a
2a
CN
H2N
MeO
Cl
1c
O
Cl
O
O
O
CN
4
3d, 55
CN
H2N
1d
O
S
O
O
O
CN
S
5
6
2a
2a
3e, 53
3f, 49
CN
H2N
1e
O
O
O
O
O
CN
O
CN
H2N
1f
O
O
O
O
CN
7
2a
3g, 42
CN
H2N
1g
O
a
Yield of isolated product based on the alkene 2a.
H2 and H3 protons of 3h–m Jtrans¼6.0–6.6 Hz, so 2-thienyl
pathway i forms J, which is an allylic radical intermediate
product. 2-Vinylphenyl substituted 2,3-dihydrofuran-3-
carboxamide L is produced as a result of cyclization of car-
bocation K. Allylic radical intermediate product M formed
by the reaction of C with 2e via pathway ii is oxidized to car-
bocation N with manganese(III) acetate, and compound O is
formed by the intramolecular cyclization following this.
Similarly, the secondary radical intermediate product P
and benzylic radical intermediate product R are formed by
the addition of a-carbon radical to 2e via pathways iii and
iv, respectively. These intermediate products form 2,3-dihy-
drofurans Q and S as a result of the same two steps as ex-
plained above. The H2 protons of Q and S are expected to
be seen as doublet peaks, whereas, triplet peaks are observed
in the 1H NMR spectra of isolated compounds. Thus, we de-
cided that Q and S compounds are not formed. On the other
hand, it is difficult to determine these two compounds
and carboxamide groups are in trans position.
2,3-Dihydrofurans containing heterocycles are produced in
the reactions of 3-oxopropanenitriles using manganese(III)
acetate with 2a and 2c but no product is formed in the
reactions of 1a–h under the same experimental conditions
with (2E)-3-phenylacrylamide 2d. On the other hand, in
the cyclization reactions of (2E,4E)-5-phenylpenta-2,4-
dienamide 2e, which is an a,b,g,d-unsaturated amide, we
obtained dihydrofuran-3-carboxamides as a mixture of
diastereomers. An a-carbon radical formed from 3-oxopro-
panenitrile via manganese(III) acetate can be added into
2e in four different ways and as a result of these different
paths, different cyclization products can be formed. The pro-
posed reaction mechanism is given in Scheme 2. According
to this mechanism, adding the a-carbon radical in 2e by

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E. V. Burgaz et al. / Tetrahedron 63 (2007) 7229–7239
Table 2. Synthesis of 2-(2-thienyl)-4-cyano-2,3-dihydrofuran-3-carboxamides 3h–m
Entry
3-Oxopropanenitrile
a,b-Unsaturated amide
4-Cyano-2,3-dihydrofuran-3-carboxamide
Product and
yield,a %
S
O
O
O
CN
S
1
3h, 47
3i, 49
NH2
H2N
CN
2c
1a
O
S
OMe
O
O
CN
2
3
2c
CN
O
H2N
MeO
1c
O
S
S
O
CN
CN
S
2c
3j, 43
CN
H2N
S
1e
O
O
O
O
O
4
5
2c
2c
3k, 34
3l, 45
CN
O
H2N
S
1h
O
O
O
CN
O
CN
H2N
1f
O
S
O
O
CN
6
2c
3m, 36
CN
H2N
1g
O
a
Yield of isolated product based on the alkene 2c.
exactly using only their 1H NMR spectra since the coupling
constant and chemical shift values of H-2, H-3 and olefinic
protons of compounds L and O are very close to each other.
So, we differentiated these compounds using HMBC spec-
tra. The amide carbonyl is coupled with H-2 and H-3, but
not with olefinic protons in these spectra. As a result, we
decided that the isolated compounds are 2-vinylphenyl
substituted 2,3-dihydrofuran-3-carboxamides L, and they
are formed via pathway i. Although both intermediate prod-
ucts J and M are allylic radicals, only the cyclization product
of J is produced. This shows that the a-carbon radical is
added to 2e in a way to form a more stable allylic radical in-
termediate product (by choosing the one which is conjugated
with the phenyl group).
LC–MS. Moreover, it is obvious that they are not geometric
isomers since both of the isomers have trans coupling
(J¼15.6–16.0 Hz) between Ha and Hb olefinic protons.
1
However, H NMR spectra show that H-2 and H-3 protons
of major products have trans coupling (J¼6.0–7.5 Hz) and
that of minor products have cis coupling (J¼9.6–10.0 Hz).
Based on these data it is concluded that the obtained com-
pounds are mixtures of trans and cis diastereomers of which
we determined the ratio (approximately 75:25) by 1H NMR
spectra.
As a result, here we studied the oxidative cyclization of
derivatives of phenyl, 2-thienyl, 2-furyl, 2-(5-methylfuryl),
and vinylphenyl substituted a,b-unsaturated acrylamides
with various 3-oxopropanenitriles via manganese(III) ace-
tate. No product could be obtained in the radical reactions
of 2-furyl (2b) and phenyl (2d) substituted acrylamides.
However, we regio- and stereoselectively obtained polyfunc-
tional 4-cyano-2,3-dihydrofuran-3-carboxamides as a result
of the reactions of other unsaturated amides (2a, 2c and 2e).
In the oxidative cyclizations of (2E,4E)-5-phenylpenta-
2,4-dienamide 2e with 3-oxopropanenitriles, we obtained
The oxidative cyclizations of 3-oxopropanenitriles with
2e produced 2-vinylphenyl substituted 2,3-dihydrofuran-3-
carboxamides L (4 and 5), as a mixture of two isomers,
which cannot be isolated from each other by chromato-
graphical methods, in moderate yields (Table 3). It is seen
that both of these isomer protons give similar couples in
HMBC spectra and have the same molecular weights in

E. V. Burgaz et al. / Tetrahedron 63 (2007) 7229–7239
7233
Mn+2
Mn+2
Ha
Ph
Hb
O
O
N
N
Mn(OAc)3
O
Ar
Ar
Ar
+
2
3
CONH2
CONH2
CN
H2NOC
(trans+cis)
J
K
L
4a-e : trans
5a-e : cis
Ph
Ph
i
Mn+2
O
O
H2NOC
Ph
Ar
Mn+2
N
iii
O
Ar
N
C
CN
Ar
Ph
Q
CONH2
P
iii
ii
iv
i
Ph
Mn+2
O
O
Ar
Ph
O
N
iv
2e
Ar
NH2
CN
CONH2
H2NOC
S
Ph
R
ii
Mn+2
Mn+2
O
O
H2NOC
N
N
O
Mn(OAc)3
Ar
Ar
Ar
+
Ph
Ph
Ph
CN
M
N
O
CONH2
Scheme 2. Mechanism for the oxidative cyclization of 3-oxopropanenitrile with (2E,4E)-5-phenylpenta-2,4-dienamide 2e.
CONH2
2-vinylphenyl substituted 4-cyano-2,3-dihydrofuran-3-car-
boxamides as diastereomeric mixtures and we proposed a
reaction mechanism for the formation of these compounds.
All reagents, 3-(4-chlorophenyl)-3-oxopropanenitrile, 1-
benzofuran-2-carboxylic acid and (2E)-3-phenylacrylamide
were purchased from Sigma–Aldrich.
3.1.1. General procedure for unsaturated amides. a,b-
Unsaturated amides 2a, 2b and 2e are synthesized according
to the method explained below. To a solution of carboxylic
acid in 100 mL chloroform was added thionyl chloride
(11 mL, 0.15 mol, freshly distilled) at room temperature.
The mixture was allowed to stand for 12 h. Then the solution
of acyl chloride in chloroform was added slowly into a solu-
tion of 100 mL ammonia (35%) containing sodium hydrox-
ide (8 g, 0.2 mol), which was cooled in ice bath and stirred
vigorously. Amide which was separated is filtered and
washed with 50 mL water. Additional solids were obtained
from chloroform solution.
3. Experimental
3.1. General
Melting points were determined on a Gallenkamp capillary
melting point apparatus. IR spectra (KBr disc, CHCl3)
were obtained with a Matson 1000 FT-IR spectrometer in
the 400–4000 cmꢀ1 range with 4 cmꢀ1 resolution. 1H NMR
(400 MHz) and 13C NMR (100 MHz) spectra were recorded
on a Bruker Avance DPX-400 MHz and Varian Mercury-400
High performance Digital FT-NMR spectrophotometers.
The mass spectra were measured on a Waters 2695 Alliance
HPLC, Waters micromass 2Q (ESI+) spectrophotometer.
Elemental analyses were performed on a Leco 932 CHNS-
O instrument. Thin layer chromatography (TLC) was
performed on Merck aluminium-packed silica gel plates.
Purification of products was performed by column chro-
matography on silica gel (Merck silica gel 60, 40–60 mm)
or preparative TLC on silica gel of Merck (PF254–366 nm).
3.1.1.1. Synthesis of (2E)-3-(5-methyl-2-furyl)acryl-
amide 2a.13 (2E)-3-(5-Methyl-2-furyl)acrylic acid was
prepared from the reaction of 5-methyl-furfural (5-methyl-
2-furaldehyde) and malonic acid described in the litera-
ture.13,14 Compound 2a was produced from this acid, which
is explained above. Yield (12.8 g) 85% as a white solid (2a),
mp 130–132 ꢁC from EtOH/H2O (lit. mp 130–132 ꢁC from

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E. V. Burgaz et al. / Tetrahedron 63 (2007) 7229–7239
Table 3. Synthesis of 2-(2-vinylphenyl)-4-cyano-2,3-dihydrofuran-3-carboxamides 4 and 5
Entry
3-Oxopropanenitrile
Unsaturated amide
4-Cyano-2,3-dihydrofuran-3-carboxamide
Yield,a %
(trans:cis)b
Ph
O
O
O
NH2
CN
1
30 (74:26)
40 (76:24)
31 (76:24)
H2N
CN
4a + 5a
2e
Ph
1a
O
Ph
Cl
O
O
CN
2
2e
H2N
CN
4b + 5b
Cl
1d
O
Ph
S
O
O
CN
S
3
2e
CN
H2N
1e
O
4c + 5c
Ph
O
O
O
CN
O
4
2e
24 (76:24)
H2N
CN
1h
O
4d + 5d
Ph
O
O
O
CN
O
5
2e
30 (72:28)
CN
H2N
O
1f
4e + 5e
a
Yields of isolated product based on the alkene 2e.
Diastereomeric ratio is determined by 1H NMR spectra.
b
acetone).16 dH (400 MHz, CDCl3) 7.15 (1H, d, J¼15.2 Hz,
Holefin), 6.54 (1H, s, NH), 6.25 (1H, d, J¼3.6 Hz, arom.
CH), 6.20 (1H, d, J¼15.2 Hz, Holefin), 5.96 (1H, s, NH),
5.90 (1H, d, J¼4.0 Hz, arom. CH), 2.18 (3H, s, CH3).
3.1.1.2. Synthesis of (2E)-3-(2-furyl)acrylamide 2b.15
(2E)-3-(2-Furyl)acrylic acid was prepared from the reaction
of furfural (2-furaldehyde) and malonic acid described in
the literature.16 Compound 2b was produced from this acid,
which is explained above. Yield (12.6 g) 92% as a white solid
(2b), mp 171–173 ꢁC recrystallization from MeOH/H2O (lit.
mp 168 ꢁC from H2O).15a dH (400 MHz, CDCl3) 7.47 (1H, d,
J¼2.0 Hz, arom.CH), 7.45 (1H, d, J¼15.2 Hz, Holefin), 6.61
(1H, d, J¼3.6 Hz, arom.CH), 6.47 (1H, dd, J¼3.6, 2.0 Hz,
arom.CH), 6.37(1H, d, J¼15.2 Hz, Holefin), 5.84(2H, s, NH2).
prepared from the reaction of (2E)-3-phenylacrylaldehyde
and malonic acid in pyridine/piperidine described in the lit-
erature.18 Compound 2e was produced from this acid, which
is explained above. Yield (12.3 g) 71% as a white solid (2e),
mp 188–189 ꢁC recrystallization from MeOH/H2O (lit. mp
185 ꢁC from ethanol).17e dH (400 MHz, CDCl3) 7.49–7.45
(3H, m, arom. CH and NH overlap), 7.38–7.30 (3H, m,
arom. CH), 7.14 (1H, s, NH), 6.93 (1H, d, J¼15.2 Hz,
H5), 6.89 (1H, d, J¼15.2 Hz, H4), 6.04 (2H, d, J¼
14.8 Hz, H2 and H3).
3.1.2. Synthesis of 3-(4-methylphenyl)-3-oxopropane-
nitrile 1b.19 A suspension of methyl 4-methylbenzoate
(15 g, 0.1 mol) and NaH (8 g, 0.2 mol, 60 wt % in white
oil) in 100 mL dry toluene is heated up to 90 ꢁC. Then under
vigorous stirring acetonitrile (10.4 mL, 0.2 mol) was added
to the suspension within 2 h. Stirring was continued subse-
quently at this temperature until the evolution of hydrogen
3.1.1.3. Synthesis of (2E,4E)-5-phenylpenta-2,4-dien-
amide 2e.15a,17 (2E,4E)-5-Phenylpenta-2,4-dienoic acid was

E. V. Burgaz et al. / Tetrahedron 63 (2007) 7229–7239
7235
ceased (6 h). After cooling to room temperature, it is filtered
with suction and washed with 20 mL Et2O. The solid mate-
rial was dissolved in 100 mL of water and cooling ice/salt
mixture. Then HCl 15% was added until pH value of the so-
lution becomes 2 and in a manner that its temperature shall
not exceed 5 ꢁC. The precipitated solids were filtered off
with suction and washed with water until they become neu-
tral, then recrystallized from ethanol/H2O to give 1b (11.0 g,
69%), mp 106–108 ꢁC (lit. mp 103–104 ꢁC from ethanol).19a
148.3, 143.0, 129.6, 127.7, 124.8, 117.5 (CN), 111.7,
107.0, 79.7, 78.2 (C2), 53.7 (C3), 21.9 (Me), 13.9 (Me);
m/z (ESI+) 309 (MH+, %100).
3.1.4.3. trans-4-Cyano-5-(4-methoxyphenyl)-50-methyl-
2,3-dihydro-2,20-bifuran-3-carboxamide (3c). Yield 64%
(210 mg) as a light brown solid, mp 170–171 ꢁC (n-hexane/
EtOAc). Found: C, 66.79; H, 5.04; N, 8.42. C18H16N2O4 re-
quires C, 66.66; H, 4.97; N, 8.64%; nmax (KBr disc) 3389
(NH), 3194 (NH), 2198 (CN), 1664 (C]O), 1610 (NH),
1259 (C–O–C), 1178 (C–O–C), 831, 787; dH (400 MHz,
CDCl3) 7.87 (2H, d, J¼8.8 Hz, arom.), 6.86 (2H, d,
J¼8.8 Hz, arom.), 6.66 (1H, s, NH), 6.34 (1H, d, J¼
3.2 Hz, arom.), 6.17 (1H, s, NH), 6.03 (1H, d, J¼7.6 Hz,
H2), 5.91 (1H, dq, J¼3.2, 0.8 Hz, arom.), 4.24 (1H, d, J¼
7.6 Hz, H3), 3.79 (3H, s, OMe), 2.24 (3H, s, Me); dC
(100 MHz, CDCl3) 171.2 (C]O), 167.7 (C5), 162.5,
154.2, 148.4, 129.6, 120.1, 117.7 (CN), 114.2, 111.6,
110.0, 106.9 (C4), 79.7 (C2), 55.6 (OMe), 53.5 (C3), 13.9
(Me); m/z (ESI+) 325 (MH+, %100).
3.1.3. Synthesis of 3-(2-benzofuroyl)-3-oxopropanenitrile
1f.20 3-(2-Benzofuroyl)-3-oxopropanenitrile (1f) was prepared
by the method described above. Methyl 1-benzofuran-2-
carboxylate was prepared from the reaction of 1-benzo-
furan-2-carboxylic acid and MeOH in HCl described in the
literature.21 Yield (17.2 g) 93% as a light brown solid (1f),
mp 148 ꢁC from acetone (lit. mp 148.5 ꢁC from acetone).20
3.1.4. General procedure for the synthesis of 4-cyano-2,3-
dihydrofuran-3-carboxamides. A solution of mangane-
se(III) acetate dihydrate (0.83 g, 3 mmol) in 15 mL of
glacial acetic acid was heated under nitrogen atmosphere
at 80 ꢁC until it dissolved. After the solution was cooled
down to 70 ꢁC, a solution of 3-oxopropanenitrile (2 mmol)
and alkene (1 mmol) in acetic acid was added to this mix-
ture. The reaction was completed when dark brown colour
of the solution changed to red colour (in 30–60 min). Water
(20 mL) was added to this solution and extracted with CHCl3
(3ꢂ20 mL). The combined organic phases were neutralized
with satd NaHCO3 solution, and dried over anhydrous
Na2SO4 and evaporated. Crude products were purified by
column chromatography on silica gel or preparative TLC
(20ꢂ20 cm plates, 2 mm thickness) using n-hexane/EtOAc
(1:1) as eluent.
3.1.4.4. trans-5-(4-Chlorophenyl)-4-cyano-50-methyl-
2,3-dihydro-2,20-bifuran-3-carboxamide (3d). Yield 55%
(180 mg) as a light brown solid, mp 200–202 ꢁC (n-hexane/
EtOAc). Found: C, 62.02; H, 4.19; N, 8.54. C17H13ClN2O3
requires C, 62.11; H, 3.99; N, 8.52%; nmax (KBr disc)
3401 (NH), 3316 (NH), 2208 (CN), 1674 (C]O), 1616
(C]C), 1236 (C–O–C), 910; dH (400 MHz, CDCl3) 7.55
(2H, d, J¼8.8 Hz, arom.), 7.04 (2H, d, J¼8.8 Hz, arom.),
6.97 (1H, s, NH), 6.12 (1H, s, NH), 6.06 (1H, d, J¼3.2 Hz,
arom.), 5.73 (1H, d, J¼7.6 Hz, H2), 5.63 (1H, dq, J¼3.2,
0.8 Hz, arom.), 4.02 (1H, d, J¼7.6 Hz, H3), 1.95 (3H, s,
Me); dC (100 MHz, CDCl3) 175.6 (C]O), 171.1 (C5),
159.0, 152.8, 142.7, 133.8, 133.7, 130.9, 121.5, 116.6
(CN), 111.7, 85.7, 84.9 (C2), 58.2 (C3), 18.6 (Me); m/z
(ESI+) 329 (MH+, %100).
3.1.4.1. trans-4-Cyano-50-methyl-5-phenyl-2,3-dihydro-
2,20-bifuran-3-carboxamide (3a). Yield 56% (170 mg) as
a white solid, mp 164–166 ꢁC (n-hexane/EtOAc). Found:
C, 69.54; H, 4.91; N, 9.22. C17H14N2O3 requires C, 69.38;
H, 4.79; N, 9.52%; nmax (KBr disc) 3439 (NH), 3304
(NH), 2206 (CN), 1672 (C]O), 1608 (C]C), 1232 (C–
O–C), 691; dH (400 MHz, CDCl3) 7.97 (2H, d, J¼6.8 Hz,
arom.), 7.48 (3H, m, arom.), 6.43 (1H, d, J¼2.0 Hz,
arom.), 6.18 (1H, d, J¼6.8 Hz, H2), 6.00 (2H, s, NH and
Ar–H, overlap), 5.88 (1H, s, NH), 4.30 (1H, d, J¼6.8 Hz,
H3), 2.31 (3H, s, Me); dC (100 MHz, CDCl3) 170.6
(C]O), 168.2 (C5), 154.5, 148.1, 132.3 (C4), 128.9,
127.8, 127.5, 117.3 (CN), 111.9, 107.0, 79.7, 79.1 (C2),
53.7 (C3), 13.9 (Me); m/z (ESI+) 295 (MH+, %100).
3.1.4.5. trans-4-Cyano-50-methyl-5-(2-thienyl)-2,3-di-
hydro-2,20-bifuran-3-carboxamide (3e). Yield 53%
(160 mg) as a yellow solid, mp 210–211 ꢁC (n-hexane/
EtOAc). Found: C, 59.64; H, 3.75; N, 9.25; S, 10.82.
C15H12N2O3S requires C, 59.99; H, 4.03; N, 9.33; S,
10.68%; nmax (KBr disc) 3399 (NH), 3314 (NH), 2208
(CN), 1674 (C]O), 1610 (C]C); dH (400 MHz, CDCl3)
7.57 (1H, dd, J¼4.0, 1.2 Hz, arom.), 7.30 (1H, dd, J¼4.8,
1.2 Hz, arom.), 7.26 (1H, s, NH), 6.87 (1H, dd, J¼5.2,
4.0 Hz, arom.), 6.38 (1H, s, NH), 6.15 (1H, d, J¼3.2 Hz,
arom.), 5.80 (1H, d, J¼7.6 Hz, H2), 5.72 (1H, dq, J¼3.2,
0.8 Hz, arom.), 4.10 (1H, d, J¼7.6 Hz, H3), 2.02 (3H, s,
Me); dC (100 MHz, DMSO-d6) 170.7 (C]O), 162.9 (C5),
154.5, 148.5, 132.6 (C4), 131.2, 129.3, 129.3, 116.6 (CN),
113.0, 107.7, 81.1, 80.2 (C2), 53.0 (C3), 14.2 (Me); m/z
(ESI+) 301 (MH+, %100).
3.1.4.2. trans-4-Cyano-50-methyl-5-(4-methylphenyl)-
2,3-dihydro-2,20-bifuran-3-carboxamide (3b). Yield 42%
(130 mg) as a white solid, mp 185–187 ꢁC (n-hexane/
EtOAc). Found: C, 70.44; H, 4.99; N, 9.22. C18H16N2O3 re-
quires C, 70.12; H, 5.23; N, 9.09%; nmax (KBr disc) 3378
(NH), 3194 (NH), 2208 (CN), 1660 (C]O), 1618 (C]C),
1564 (NH), 1254 (C–O–C), 920, 791; dH (400 MHz,
CDCl3) 7.85 (2H, d, J¼8.0 Hz, arom.), 7.23 (2H, d,
J¼8.4 Hz, arom.), 6.40 (1H, d, J¼3.2 Hz, arom.), 6.13
(1H, d, J¼7.6 Hz, H2), 6.04 (1H, s, NH), 6.00 (1H, s,
NH), 5.97 (1H, dq, J¼3.2, 0.8 Hz, arom.), 4.27 (1H, d,
J¼7.6 Hz, H3), 2.39 (3H, s, Me), 2.29 (3H, s, Me); dC
(100 MHz, CDCl3) 170.9 (C]O), 168.4 (C5), 157.4,
3.1.4.6. trans-40-Cyano-5-methyl-20,30-dihydro-2,20:50,
200-terfuran-30-carboxamide (3f). Yield 49% (160 mg) as
a yellow solid, mp 180–182 ꢁC (n-hexane/EtOAc). Found:
C, 68.36; H, 4.20; N, 8.45. C19H14N2O4 requires C, 68.26;
H, 4.22; N, 8.38%; nmax (KBr disc) 3381 (NH), 3194
(NH), 2214 (CN), 1645 (C]O), 1180 (C–O–C); dH
(400 MHz, CDCl3) 7.56 (1H, dd, J¼8.0, 0.8 Hz, arom.),
7.50 (1H, dd, J¼8.4, 1.2 Hz, arom.), 7.34 (1H, td, J¼8.4,
1.2 Hz, arom.), 7.30 (1H, s, arom.), 7.25 (1H, dd, J¼8.8,

7236
E. V. Burgaz et al. / Tetrahedron 63 (2007) 7229–7239
1.2 Hz, arom.), 6.95 (1H, s, NH), 6.38 (1H, d, J¼3.2 Hz,
arom.), 6.19 (1H, s, NH), 6.12 (1H, d, J¼7.6 Hz, H2), 5.92
(1H, dq, J¼3.2, 0.8 Hz, arom.), 4.32 (1H, d, J¼7.6 Hz,
H3), 2.23 (3H, s, Me); dC (100 MHz, CDCl3) 170.4
(C]O), 158.7 (C5), 154.5, 154.5, 147.8, 144.3, 127.4,
127.3, 124.1, 122.6, 115.8 (CN), 112.3, 112.2, 111.3,
107.0, 81.7, 81.0 (C2), 53.0 (C3), 13.9 (Me); m/z (ESI+)
335 (MH+, %100).
1217 (C–O–C); dH (400 MHz, CDCl3) 7.94 (1H, dd,
J¼3.8, 0.9 Hz, arom.), 7.60 (1H, dd, J¼5.0, 1.0 Hz,
arom.), 7.38 (1H, dd, J¼5.1, 1.1 Hz, arom.), 7.20–7.17
(2H, m, arom.), 7.05 (1H, dd, J¼5.0, 3.6 Hz, arom.), 6.50
(1H, d, J¼6.3 Hz, H2), 5.90 (1H, s, NH), 5.71 (1H, s,
NH), 4.10 (1H, d, J¼6.3 Hz, H3); dC (100 MHz, CDCl3)
170.0 (C]O), 163.0 (C5), 141.2, 131.3, 131.2, 129.1,
128.3, 127.2, 126.8, 126.5, 116.4 (CN), 83.0 (C2), 57.4
(C3); m/z (ESI+) 303 (MH+, %100).
3.1.4.7. trans-5-tert-Butyl-4-cyano-50-methyl-2,3-dihy-
dro-2,20-bifuran-3-carboxamide (3g). Yield 42% (240 mg)
as a yellow oil. Found: C, 65.54; H, 6.57; N, 10.35.
C15H18N2O3 requires C, 65.68; H, 6.61; N, 10.21%; nmax
(KBr disc) 3401 (NH), 3341 (NH), 2959, 2923, 2210 (CN),
1684 (C]O), 1616 (C]C), 1165 (C–O–C); dH (400 MHz,
CDCl3) 6.32 (1H, d, J¼3.2 Hz, arom.), 5.97 (1H, d,
J¼6.4 Hz, H2), 5.95 (1H, dq, J¼3.2, 0.4 Hz, arom.), 5.81
(1H, s, NH), 5.66 (1H, s, NH), 4.01 (1H, d, J¼6.8 Hz, H3),
2.30 (3H, s, Me), 1.29 (9H, s, Me); dC (100 MHz, CDCl3)
180.9 (C]O), 173.0 (C5), 170.7, 153.9, 148.4 (C4), 116.8
(CN), 110.8, 106.6, 79.2 (C2), 78.0, 53.5 (C3), 27.9 (Me),
13.6 (Me); m/z (ESI+) 275 (MH+, %100).
3.1.4.11.
trans-3-Cyano-5-(2-thienyl)-4,5-dihydro-
2,20-bifuran-4-carboxamide (3k). Yield 34% (100 mg) as
a light yellow solid, mp 180–182 ꢁC (n-hexane/EtOAc).
Found: C, 58.80; H, 3.34; N, 9.82; S, 11.23. C14H10N2O3S
requires C, 58.73; H, 3.52; N, 9.78; S, 11.20%; nmax (KBr
disc) 3406 (NH), 3314 (NH), 2212 (CN), 1672 (C]O),
1618 (C]C), 1242 (C–O–C); dH (400 MHz, CDCl3) 7.66
(1H, d, J¼1.5 Hz, arom.), 7.38 (1H, dd, J¼5.1, 1.0 Hz,
arom.), 7.20 (1H, d, J¼3.5 Hz, arom.), 7.07 (1H, d,
J¼3.6 Hz, arom.), 7.04 (1H, dd, J¼5.0, 3.6 Hz, arom.),
6.57 (1H, dd, J¼3.6, 1.8 Hz, arom.), 6.50 (1H, d,
J¼6.4 Hz, H5), 5.96 (1H, s, NH), 5.77 (1H, s, NH), 4.10
(1H, d, J¼6.4 Hz, H4); dC (100 MHz, DMSO-d6) 170.7
(C]O), 157.6 (C5), 147.9, 142.9, 141.3 (C4), 128.5,
128.4, 127.9, 115.9 (CN), 115.8, 113.3, 83.9, 80.4 (C2),
56.7 (C3); m/z (ESI+) 287 (MH+, %100).
3.1.4.8. trans-4-Cyano-5-phenyl-2-(2-thienyl)-2,3-di-
hydrofuran-3-carboxamide (3h). Yield 47% (140 mg) as
a white solid, mp 163–164 ꢁC (n-hexane/EtOAc). Found:
C, 63.12; H, 4.34; N, 9.76; S, 10.70. C16H12N2O2S requires
C, 64.85; H, 4.08; N, 9.45; S, 10.82%; nmax (KBr disc) 3395
(NH), 3196 (NH), 2208 (CN), 1666 (C]O), 1620 (C]C),
1234 (C–O–C), 750–691; dH (400 MHz, CDCl3) 8.00 (2H,
dd, J¼7.2, 1.5 Hz, arom.), 7.53 (1H, tt, J¼7.2, 1.3 Hz,
arom.), 7.48 (2H, t, J¼7.7 Hz, arom.), 7.37 (1H, dd,
J¼5.1, 1.1 Hz, arom.), 7.20 (1H, d, J¼3.3 Hz, arom.), 7.04
(1H, dd, J¼5.1, 3.6 Hz, arom.), 6.50 (1H, d, J¼6.4 Hz,
H2), 6.00 (1H, s, NH), 5.88 (1H, s, NH), 4.13 (1H, d,
J¼6.4 Hz, H3); dC (100 MHz, CDCl3) 170.0 (C]O),
167.9 (C5), 141.3, 132.3, 128.8, 127.6, 127.2, 127.1,
126.7, 126.3, 116.8 (CN), 82.3 (C2), 78.6, 57.7 (C3); m/z
(ESI+) 297 (MH+, %100).
3.1.4.12.
trans-5-(1-Benzofuran-2-yl)-4-cyano-2-(2-
thienyl)-2,3-dihydrofuran-3-carboxamide (3l). Yield
45% (150 mg) as a white solid, mp 183–184 ꢁC (n-hexane/
EtOAc). Found: C, 63.92; H, 3.77; N, 8.18; S, 9.08.
C18H12N2O3S requires C, 64.27; H, 3.60; N, 8.33; S,
9.53%; nmax (KBr disc) 3426 (NH), 3327 (NH), 2212 (CN),
1678 (C]O), 1643 (C]C), 1617 (N–H), 1177 (C–O–C),
752, 756; dH (400 MHz, CDCl3) 7.66 (1H, d, J¼7.8 Hz,
arom.), 7.61 (1H, d, J¼8.4 Hz, arom.), 7.45 (1H, t, J¼
7.3 Hz, arom.), 7.40 (1H, s, arom.), 7.38 (2H, d, J¼5.1 Hz,
arom.), 7.32 (1H, t, J¼7.4 Hz, arom.), 7.22 (1H, d, J¼
3.4 Hz, arom.), 7.05 (1H, dd, J¼5.0, 3.6 Hz, arom.), 6.56
(1H, d, J¼6.6 Hz, H2), 6.07 (1H, s, NH), 5.91 (1H, s, NH),
4.17 (1H, d, J¼6.6 Hz, H3); dC (100 MHz, CDCl3) 169.9
(C]O), 158.9 (C5), 155.8, 143.9, 140.8, 127.6, 127.2,
127.0, 126.8, 124.0, 122.5, 115.5 (CN), 112.2 (C4), 111.7,
83.4 (C2), 80.2, 57.2 (C3); m/z (ESI+) 337 (MH+, %100).
3.1.4.9.
trans-4-Cyano-5-(4-methoxyphenyl)-2-(2-
thienyl)-2,3-dihydrofuran-3-carboxamide (3i). Yield
49% (160 mg) as a white solid, mp 162–164 ꢁC (n-hexane/
EtOAc). Found: C, 62.12; H, 4.34; N, 8.76; S, 9.70.
C17H14N2O3S requires C, 62.56; H, 4.32; N, 8.58; S,
9.83%; nmax (KBr disc) 3379 (NH), 3192 (NH), 2204
(CN), 1664 (C]O), 1610 (C]C), 1263 (C–O–C), 831; dH
(400 MHz, CDCl3) 7.95 (2H, d, J¼9.2 Hz, arom.), 7.34
(1H, dd, J¼5.2, 1.2 Hz, arom.), 7.16 (1H, d, J¼3.6 Hz,
arom.), 7.01 (1H, dd, J¼5.2, 3.6 Hz, arom.), 6.95 (2H, d,
J¼8.8 Hz, arom.), 6.44 (1H, d, J¼6.0 Hz, H2), 5.99 (1H,
s, NH), 5.87 (1H, s, NH), 4.06 (1H, d, J¼6.4 Hz, H3), 3.85
(3H, s, Me); dC (100 MHz, CDCl3) 170.7 (C]O), 168.0
(C5), 162.9, 141.8, 129.8, 127.3, 126.8, 126.4, 119.8 (C4),
117.6 (CN), 114.4, 82.3 (C2), 57.8 (Me), 55.7 (C3); m/z
(ESI+) 327 (MH+, %100).
3.1.4.13. trans-5-tert-Butyl-4-cyano-2-(2-thienyl)-2,3-
dihydrofuran-3-carboxamide (3m). Yield 36% (100 mg)
as a yellow oil. Found: C, 61.12; H, 5.97; N, 10.03; S,
11.34. C14H16N2O2S requires C, 60.85; H, 5.84; N, 10.14;
S, 11.60%; nmax (KBr disc, CHCl3) 3414 (NH), 3335
(NH), 2210 (CN), 1683 (C]O), 1616 (C]C), 1246 (C–
O–C); dH (400 MHz, CDCl3) 7.36 (1H, d, J¼5.1 Hz,
arom.), 7.11 (1H, d, J¼3.4 Hz, arom.), 7.02 (1H, dd,
J¼5.0, 3.6 Hz, arom.), 6.35 (1H, d, J¼6.0 Hz, H2), 5.84
(2H, s, NH), 3.86 (1H, d, J¼6.0 Hz, H3), 1.36 (9H, s, Me);
m/z (ESI+) 277 (MH+, %100).
3.1.4.10. trans-4-Cyano-2,5-di-2-thienyl-2,3-dihydro-
furan-3-carboxamide (3j). Yield 43% (130 mg) as a white
solid, mp 194–196 ꢁC (n-hexane/EtOAc). Found: C, 55.86;
H, 3.34; N, 9.27; S, 20.91. C14H10N2O2S2 requires C,
55.61; H, 3.33; N, 9.26; S, 21.21%; nmax (KBr disc) 3412
(NH), 3314 (NH), 2206 (CN), 1672 (C]O), 1608 (C]C),
3.1.4.14.
trans-4-Cyano-5-phenyl-2-[(E)-2-phenyl-
vinyl]-2,3-dihydrofuran-3-carboxamide (4a). Yield 29%
(90 mg) as a yellow solid, mp 182–184 ꢁC (n-hexane/
EtOAc). Found: C, 75.72; H, 5.36; N, 8.68. C20H16N2O2
requires C, 75.93; H, 5.10; N, 8.86%; nmax (KBr disc)
3403 (NH), 3310 (NH), 2206 (CN), 1674 (C]O), 1616

E. V. Burgaz et al. / Tetrahedron 63 (2007) 7229–7239
7237
(C]C), 1234 (C–O–C), 752, 689; dH (400 MHz, CDCl3)
3.1.4.19.
thienyl)-2,3-dihydrofuran-3-carboxamide
cis-4-Cyano-2-[(E)-2-phenylvinyl]-5-(2-
(5c).
7.94 (2H, d, J¼7.6 Hz), 7.48–7.21 (8H, m, arom.), 6.86
(1H, s, NH), 6.70 (1H, d, J¼15.6 Hz, Ha), 6.25 (1H, dd,
J¼15.6, 7.2 Hz, Hb), 6.14 (1H, s, NH), 5.75 (1H, t,
J¼7.2 Hz, H2), 3.87 (1H, d, J¼7.2 Hz, H3); dC (100 MHz,
CDCl3) 171.4 (C]O), 167.4 (C5), 136.1, 134.1, 132.7,
129.8, 129.4, 129.1, 127.8, 127.6, 127.5, 126.7, 117.2
(CN), 87.5 (C2), 82.0 (C4), 55.5 (C3); m/z (ESI+) 317
(MH+, %100).
dH
(400 MHz, CDCl3) 7.98 (1H, dd, J¼4.0, 0.4 Hz, arom.),
7.60 (1H, dd, J¼4.8, 0.4 Hz, arom.), 7.43–7.26 (5H, m,
arom.), 7.17 (1H, dd, J¼4.8, 3.2 Hz, arom.), 6.81 (1H, d,
J¼15.2 Hz, Ha), 6.37 (1H, dd, J¼16.0, 8.0 Hz, Hb), 5.78
(1H, s, NH), 5.65 (2H, m, H2 and NH, overlap), 4.12 (1H,
d, J¼10.0 Hz, H3); dC (100 MHz, DMSO-d6) 170.5
(C]O), 160.1 (C5), 137.2, 134.9, 131.7, 131.1, 129.8,
129.1, 129.3, 129.2, 127.6, 126.6, 117.3 (CN), 87.5 (C2),
81.2 (C4), 53.6 (C3).
3.1.4.15. cis-4-Cyano-5-phenyl-2-[(E)-2-phenylvinyl]-
2,3-dihydrofuran-3-carboxamide (5a). dH (400 MHz,
CDCl3) 7.94 (2H, d, J¼7.6 Hz), 7.48–7.21 (8H, m, arom.),
6.66 (1H, s, NH), 6.73 (1H, d, J¼15.6 Hz, Ha), 6.39 (1H,
dd, J¼16.0, 7.4 Hz, Hb), 6.05 (1H, s, NH), 5.52 (1H,
t, J¼9.6 Hz, H2), 4.13 (1H, d, J¼10.0 Hz, H3); dC
(100 MHz, DMSO-d6) 170.0 (C]O), 168.0 (C5), 136.3,
135.5, 132.6, 129.7, 129.4, 129.1, 128.0, 127.5, 127.4,
123.7, 117.7 (CN), 86.0 (C2), 82.6 (C4), 54.0 (C3).
3.1.4.20. trans-3-Cyano-5-[(E)-2-phenylvinyl]-4,5-di-
hydro-2,20-bifuran-4-carboxamide (4d). Yield 24%
(140 mg) as a yellow solid, mp 231–233 ꢁC (n-hexane/
EtOAc). Found: C, 70.45; H, 4.32; N, 9.27. C18H14N2O3 re-
quires C, 70.58; H, 4.61; N, 9.15%; nmax (KBr disc) 3352
(NH), 3194 (NH), 2210 (CN), 1678 (C]O), 1649 (C]C),
1124 (C–O–C), 754, 691; dH (400 MHz, CDCl3) 7.57 (1H,
d, J¼1.6 Hz, arom.), 7.35 (1H, d, J¼6.8 Hz, arom.), 7.30–
7.21 (4H, m, arom.), 7.01 (1H, d, J¼3.2 Hz, arom.), 6.80
(1H, s, NH), 6.70 (1H, d, J¼15.6 Hz, Ha), 6.50 (1H, dd,
J¼3.6, 1.6 Hz, arom.), 6.23 (1H, dd, J¼16.0, 7.6 Hz, Hb),
6.06 (1H, s, NH), 5.75 (1H, t, J¼7.0 Hz, H2), 3.82 (1H, d,
J¼6.8 Hz, H3); dC (100 MHz, CDCl3) 170.8 (C]O),
159.0 (C5), 145.9, 135.4, 134.4, 128.7, 126.9, 124.8,
115.9, 115.2 (CN), 112.1, 87.3 (C2), 78.3 (C4), 54.9 (C3);
m/z (ESI+) 307 (MH+, %100).
3.1.4.16.
trans-5-(4-Chlorophenyl)-4-cyano-2-[(E)-
2-phenylvinyl]-2,3-dihydrofuran-3-carboxamide (4b).
Yield 40% (140 mg) as a white solid, mp 211–213 ꢁC (n-
hexane/EtOAc). Found: C, 68.73; H, 4.25; N, 8.08.
C20H15ClN2O2 requires C, 68.48; H, 4.31; N, 7.99%; nmax
(KBr disc) 3395 (NH), 3306 (NH), 3204, 2208 (CN), 1674
(C]O), 1616 (C]C), 1232 (C–O–C), 835, 754 (C–Cl);
dH (400 MHz, CDCl3) 7.96 (2H, d, J¼8.4 Hz, arom.),
7.46–7.29 (7H, m, arom.), 6.78 (1H, d, J¼15.6 Hz, Ha),
6.29 (1H, dd, J¼15.6, 7.2 Hz, Hb), 5.90 (1H, s, NH), 5.87
(1H, t, J¼7.2 Hz, H2), 5.71 (1H, s, NH), 3.85 (1H, d,
J¼7.2 Hz, H3); dC (100 MHz, DMSO-d6) 171.2 (C]O),
168.4 (C5), 166.1, 137.3, 136.1, 134.2, 130.0, 129.4,
129.3, 129.2, 127.6, 126.6, 117.0 (CN), 87.7 (C2), 82.6
(C4), 55.6 (C3); m/z (ESI+) 351 (MH+, %100).
3.1.4.21.
cis-3-Cyano-5-[(E)-2-phenylvinyl]-4,5-di-
hydro-2,20-bifuran-4-carboxamide (5d). dH (400 MHz,
CDCl3) 7.57 (1H, d, J¼1.6 Hz, arom.), 7.35 (1H, d,
J¼6.8 Hz, arom.), 7.30–7.21 (4H, m, arom.), 7.02 (1H, d,
J¼3.6 Hz, arom.), 6.72 (1H, d, J¼16.0 Hz, Ha), 6.63 (1H,
s, NH), 6.50 (1H, dd, J¼3.6, 1.2 Hz, arom.), 6.36 (1H, dd,
J¼16.0, 8.0 Hz, Hb), 5.98 (1H, s, NH), 5.52 (1H, t,
J¼9.6 Hz, H2), 4.10 (1H, d, J¼10.0 Hz, H3); dC
(100 MHz, CDCl3) 169.8 (C]O), 160.1 (C5), 143.1,
136.4, 135.5, 128.7, 127.1, 121.6, 115.7, 115.4 (CN),
112.1, 86.9 (C2), 79.6 (C4), 53.7 (C3).
3.1.4.17.
cis-5-(4-Chlorophenyl)-4-cyano-2-[(E)-2-
phenylvinyl]-2,3-dihydrofuran-3-carboxamide (5b). dH
(400 MHz, CDCl3) 7.96 (2H, d, J¼8.4 Hz, arom.), 7.46–7.29
(7H, m, arom.), 6.80 (1H, d, J¼15.6 Hz, Ha), 6.40 (1H, dd,
J¼15.6, 8.0 Hz, Hb), 5.75 (1H, s, NH), 5.68 (1H, s, NH),
5.61 (1H, t, J¼9.6 Hz, H2), 4.12 (1H, d, J¼10.0 Hz, H3);
dC (100 MHz, DMSO-d6) 69.8 (C]O), 168.4 (C5), 166.8,
137.2, 136.3, 135.6, 129.9, 129.5, 129.3, 129.1, 127.5,
126.7, 117.4 (CN), 86.1 (C2), 83.3 (C4), 54.1 (C3).
3.1.4.22. trans-5-(1-Benzofuran-2-yl)-4-cyano-2-[(E)-
2-phenylvinyl]-2,3-dihydrofuran-3-carboxamide
(4e).
Yield 30% (110 mg) as a white solid, mp 227–229 ꢁC
(n-hexane/EtOAc). Found: C, 74.82; H, 4.26; N, 7.58.
C22H16N2O3 requires C, 74.15; H, 4.53; N, 7.86%; nmax
(KBr disc) 3406 (NH), 3318 (NH), 2212 (CN), 1676
(C]O), 1618 (C]C), 1253 (C–O–C), 750, 691; dH
(400 MHz, CDCl3) 7.74 (1H, s, NH), 7.62 (3H, m, arom.),
7.49 (1H, d, J¼8.33 Hz, arom.), 7.37–7.20 (6H, m, arom.),
6.89 (1H, s, NH), 6.68 (1H, d, J¼15.8 Hz, Ha), 6.30 (1H,
dd, J¼15.8, 7.5 Hz, Hb), 5.68 (1H, t, J¼7.5 Hz, H2), 3.97
(1H, d, J¼7.5 Hz, H3); dC (100 MHz, CDCl3) 171.0
(C]O), 158.2 (C5), 155.5, 144.5, 136.2, 134.7, 129.4,
129.3, 128.3, 127.6, 127.5, 126.2, 124.9, 123.6, 115.8
(CN), 112.4, 111.4, 88.7 (C2), 84.5 (C4), 55.2 (C3); m/z
(ESI+) 357 (MH+, %100).
3.1.4.18.
trans-4-Cyano-2-[(E)-2-phenylvinyl]-5-(2-
thienyl)-2,3-dihydrofuran-3-carboxamide (4c). Yield
31% (200 mg) as a yellow solid, mp 235–237 ꢁC (n-hex-
ane/EtOAc). Found: C, 66.83; H, 4.06; N, 8.67; S, 9.88.
C18H14N2O2S requires C, 67.06; H, 4.38; N, 8.69; S,
9.95%; nmax (KBr disc) 3412 (NH), 3310 (NH), 3208,
2208 (CN), 1674 (C]O), 1612 (C]C), 1213 (C–O–C),
962, 750, 712; dH (400 MHz, CDCl3) 7.93 (1H, dd, J¼3.6,
0.8 Hz, arom.), 7.58 (1H, dd, J¼4.8, 0.8 Hz, arom.), 7.43–
7.26 (5H, m, arom.), 7.17 (1H, dd, J¼4.8, 3.6 Hz, arom.),
6.78 (1H, d, J¼15.6 Hz, Ha), 6.29 (1H, dd, J¼16.0,
7.6 Hz, Hb), 5.86 (2H, t, J¼6.8 Hz, H2 and NH, overlap),
5.61 (1H, s, NH), 3.84 (1H, d, J¼6.8 Hz, H3); dC
(100 MHz, DMSO-d6) 171.2 (C]O), 162.4 (C5), 136.1,
134.4, 132.4, 131.1, 129.6, 129.4, 129.3, 129.2, 127.6,
126.5, 116.9 (CN), 88.2 (C2), 80.3 (C4), 55.2 (C3); m/z
(ESI+) 323 (MH+, %100).
3.1.4.23. cis-5-(1-Benzofuran-2-yl)-4-cyano-2-[(E)-2-
phenylvinyl]-2,3-dihydrofuran-3-carboxamide (5e). dH
(400 MHz, CDCl3) 7.62 (3H, m, arom.), 7.49 (1H, d,
J¼8.33 Hz, arom.), 7.44 (1H, s, NH), 7.37–7.20 (7H, m,
arom.), 6.75 (2H, m, Ha and NH, overlap), 6.38 (1H, dd,

7238
E. V. Burgaz et al. / Tetrahedron 63 (2007) 7229–7239
V.; Treesa, P. M.; Maliakal, D.; Rath, N. P. Tetrahedron 2001,
57, 7705–7710; (f) Tseng, C.-H.; Wu, Y.-L.; Chuang, C.-P.
Tetrahedron 2002, 58, 7625–7633; (g) Liao, Y.-J.; Wu, Y.-L.;
Chuang, C.-P. Tetrahedron 2003, 59, 3511–3520; (h)
Kobayashi, K.; Nagase, K.; Morikawa, O.; Konishi, H.
Heterocycles 2003, 60, 939–946; (i) Wu, Y.-L.; Chuang, C.-P.
Tetrahedron 2004, 60, 1841–1847.
J¼16.0, 8.5 Hz, Hb), 5.58 (1H, t, J¼10.3 Hz, H2), 4.22 (1H,
d, J¼10.3 Hz, H3); dC (100 MHz, CDCl3) 169.7 (C]O),
158.9 (C5), 155.5, 144.5, 136.0, 135.2, 129.5, 129.1,
128.5, 127.7, 127.5, 126.4, 125.0, 123.2, 116.4 (CN),
112.4, 111.2, 87.2 (C2), 83.7 (C4), 53.7 (C3).
5. (a) Corey, E. J.; Ghosh, A. K. Chem. Lett. 1987, 223–226; (b)
Melikyan, G. G.; Sargsyan, A. B.; Badonyan, S. O. Chem.
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Acknowledgements
This work was supported by an Ankara University Scientific
Research Project (BAP 20060705114).
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