One-pot, three-component reaction of isocyanides, dialkyl acetylenedicarboxylates, and non-cyclic anhydrides: Synthesis of 2,5-diaminofuran derivatives and dialkyl (E)-2-[(N-acyl-N-alkylamino)carbonyl]- 2-butenedioates

Article abstract of DOI:10.1007/s00706-010-0257-9

Isocyanides, dialkyl acetylenedicarboxylates, and non-cyclic anhydrides, for example acetic anhydride or benzoic anhydride, react in one-pot to afford 2,5-diaminofuran derivatives and dialkyl (E)-2-[(N-acyl-N-alkylamino)carbonyl]- 2-butenedioates in fairl

Full text of DOI:10.1007/s00706-010-0257-9

Monatsh Chem (2010) 141:333–338
DOI 10.1007/s00706-010-0257-9
ORIGINAL PAPER
One-pot, three-component reaction of isocyanides, dialkyl
acetylenedicarboxylates, and non-cyclic anhydrides:
synthesis of 2,5-diaminofuran derivatives and dialkyl
(E)-2-[(N-acyl-N-alkylamino)carbonyl]-2-butenedioates
•
Mohammad Bayat Hossein Imanieh
•
•
Nader Zabarjad Shiraz Mohammad Shah Qavidel
Received: 17 March 2009 / Accepted: 20 January 2010 / Published online: 27 February 2010
Ó Springer-Verlag 2010
Abstract Isocyanides, dialkyl acetylenedicarboxylates,
and non-cyclic anhydrides, for example acetic anhydride or
benzoic anhydride, react in one-pot to afford 2,5-diaminofu-
ran derivatives and dialkyl (E)-2-[(N-acyl-N-alkylamino)
carbonyl]-2-butenedioates in fairly good yields at room
temperature.
Polysubstituted furans play an important role in organic
chemistry, not only because of their presence as key
structural units in many natural products [15] and in
important pharmaceuticals [16] but also because of their
use in synthetic chemistry as building blocks. For this
reason the synthesis of polysubstituted furans continues to
attract the interest of many synthetic chemists.
Keywords Isocyanides Á Acetylenic ester Á
Acetic anhydride Á Multicomponent reaction
Although the trapping of the 1:1 intermediate formed
between dialkyl acetylenedicarboxylates and isocyanides
with aldehydes [17], aromatic anhydrides [18, 19], 1,3-
diones [20], benzoyl chlorides [21], benzoyl cyanides [22],
quinones [23], malimide, and succinimides [24] has been
studied in detail by a number of research groups [6–10],
trapping of the initial 1:1 intermediate formed with acetic
or benzoic anhydride has not been reported.
Introduction
Multicomponent reactions are well established as a pow-
erful tool for rapid construction of complex and structurally
diverse compounds from relatively simple building blocks
[1–3]. Simple procedures, high atom-economy, chemical
efficiency, and convergence are typical features of such
one-pot condensations of at least three different starting
materials. Because of the remarkably high purity of librar-
ies, multicomponent reactions are well-suited for both
combinatorial chemistry and high-speed parallel synthesis,
and therefore have high exploratory power [4, 5]. Isocya-
nide-based [6–10] multicomponent reactions, especially,
have been emerging fields of interest in the last decade, but
the construction of heterocycles via multicomponent reac-
tions has also attracted interest recently [11–14].
Dimethyl acetylenedicarboxylate (DMAD) and isocya-
nides undergo a variety of cycloadditions with a third
component containing a carbonyl group to form diverse
heterocyclic scaffolds. For example the reaction of
DMAD, an isocyanide, and phthalic anhydride derivatives
produces benzofused spirolactones [18, 19]. We planned
to test a similar reaction between DMAD, isocyanide, and
acetic anhydride or benzoic anhydride for construction of
iminolactone derivatives, which was also based on the
work of Esmaili and Bodaghi [18] and Shaabani et al.
[19]. In these experiments we found that the reaction was
different. We now report a simple one-pot synthesis of
2,5-diaminofuran derivatives and highly functionalized
enone compounds using alkyl isocyanides 1 and dialkyl
acetylenedicarboxylates 2 in the presence of acetic
anhydride (3a) or benzoic anhydride (3b) as trapping
agents for the reactive zwitterionic intermediate. This
three-component condensation reaction produces highly
functionalized compounds 4 and 5 in fairly good yields
(Scheme 1).
M. Bayat (&) Á H. Imanieh Á M. S. Qavidel
Department of Chemistry, Imam Khomeini International
University, Qazvin, Iran
e-mail: bayat_mo@yahoo.com
N. Z. Shiraz
Department of Chemistry, Islamic Azad University, Tehran, Iran
123

334
M. Bayat et al.
The 1H NMR spectrum of 5b exhibits five sharp singlets
for two tert-butyl groups (d = 1.36 and 1.42 ppm), the
acetoxy group (d = 1.96 ppm), and two methoxy groups
O
R'O2C
O
CO2R'
CO2R'
C
O
O
CO2R'
H
R"
R"
CH2Cl2
r.t.
O
2 R-N=C:
+
+
+
H
N
R"
N
R
C
R"
N
R
O
CO2R'
CO2R'
O
R
1
2
3
4
5
(d = 3.77 and 3.84 ppm), and
a
broad signal
(d = 6.90 ppm) for the NH group. The 13C NMR spectrum
of 5b showed 14 distinct resonances in agreement with the
proposed structure. Four signals (d = 85.91, 113.63,
139.66, and 159.61 ppm) are readily assigned to the furan
carbon atoms. The mass spectra of compounds 4 and 5
displayed molecular ion peaks at appropriate m/z values.
A plausible mechanism for the formation of 4 is shown
in Scheme 2. On the basis of the well-established chem-
istry of isocyanides [25–28] it is reasonable to assume that
compound 4 results from initial addition of alkyl isocya-
nide 1 to the acetylenic ester and subsequent protonation of
the 1:1 adduct 6 by acid from hydrolysis of the anhydride,
followed by attack of the carboxylate anion of the posi-
tively charged ion 7 to form an imidoyl carboxylate 8,
which undergoes rearrangement [29, 30] to produce the
enone 4. Compound 4 is trapped by isocyanide to give the
2,5-diaminofuran derivative 5.
4, 5
a
b
c
R
R'
R"
Me
Me
Me
Ph
Ratio 4:5
7.8:1
1:8
Cyclohexyl
t-Bu
Me
Me
t-Bu
Et
t-Bu
1:2
d
e
t-Bu
1:0
t-Bu
Me
Et
Ph
8.5:1.2
0:1
f
t-Bu
Me
Ph
g
h
i
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Et
1:0
Me
Me
t-Bu
Et
Ph
8:1
i-Pr
Me
Me
7.8:1
1:0
j
k
2:1
We extended our studies to various reaction conditions.
The reaction in the presence of a 1:1 mixture of anhydride
and the corresponding carboxylic acid or replacing the
anhydride by carboxylic acid resulted in better yields of
the products. When the solvent was carefully dried and the
reaction was carried out under nitrogen atmosphere,
the corresponding 2,5-dihydro-5-imino-2-alkylfuran-3,4-
dicarboxylate 9 was obtained in 30–40% yields (Scheme 3).
It is conceivable that the intermediate 6 adds to a carbonyl
group of the anhydride which undergoes cyclization to 9.
Furthermore, when few drops of water were added to the
reaction mixture, the reaction proceeded smoothly to afford
the desired products in good yields and reduced formation
of 9.
Scheme 1
Results and discussion
The one-pot, three-component condensation reactions of
alkyl isocyanides 1 with electron-deficient acetylenic esters
2 in the presence of acetic anhydride (3a) or benzoic anhy-
dride (3b) proceeded spontaneously at room temperature in
dichloromethane and was complete after 1 day, affording the
corresponding dialkyl (E)-2-[(N-acyl-N-alkylamino)car-
bonyl]-2-butenedioates
4
and dialkyl 2-(N-acyl-N-
alkylamino)-5-(alkylamino)-3,4-furandicarboxylates 5 in
In conclusion, the three-component reaction of alkyl
isocyanides with electron-deficient acetylenic esters in the
presence of acetic anhydride or benzoic anhydride provides
a simple entry to the synthesis of 2,5-diaminofuran deriv-
atives and polyfunctionalized enones of potential synthetic
interest. This procedure has the advantage that, not only is
the reaction performed under neutral conditions, but also
the substances can be mixed without any activation or
modification.
1
moderate to good yields. H NMR spectra of the crude
reaction mixture clearly indicated the formation of com-
pounds 4 and 5 even in 1:1:1 (isocyanide: DMAD: Ac2O)
experiments. The structures of compounds 4a–4k and 5a–5k
were deduced from their elemental analyses and their IR, 1H
NMR, and 13C NMR spectroscopic data. For example, the
1H NMR spectrum of 4a exhibits a multiplet for the cyclo-
hexyl ring (d = 1.24–2.20 ppm) and four sharp singlets for
the acetoxy group (d = 2.39 ppm), two methoxy groups
(d = 3.67 and 3.84 ppm), and the vinylic proton
(d = 6.61 ppm). The E configuration of the carbon–carbon
double bond in 4 is based on the chemical shift of the olefinic
proton. The 13C NMR spectrum of 4a showed 15 distinct
resonances in agreement with the proposed structure. Two
signals (d = 122.68 and 143.98) ppm are readily assigned to
the olefinic carbon atoms.
Experimental
Dialkyl acetylenedicarboxylates, alkyl isocyanides, and
other reagents and solvents used in this work were obtained
from Fluka (Buchs, Switzerland) and used without further
purification. NMR spectra were recorded with a Bruker
DRX-300 Avance instrument (299.9 MHz for 1H and
123

One-pot three-component condensation reaction
335
Scheme 2
O
O
O
R"
R"
R-N=C:
+
C
C
CO2R'
R'O2C
+
1
2
3
CO2R'
H
O
NR
+
+
_
H
CO2R'
_
R-N=C
R-N=C
HOOCR"
OOCR"
R"
O
4
R'O2C
CO2R'
R'O2C
CO2R'
6
7
8
R
N
R
:C=NR
CHCO2R'
N
H
O
O
O
O
H
CO2R'
O
O
R"
N
R
[4+1]
CO2R'
CO2R'
N
R
R"
R"
N
CO2R'
CO2R'
R
5
4
Scheme 3
O
O
O
R'O2C
CO2R'
O
R"
R"
Dry CH2Cl2
r.t.
R''
R-N=C:
+
C
C CO2R'
+
R'O2C
R
N
O
R''
O
9
75.4 MHz for 13C) with CDCl3 as solvent. Chemical shifts
are given in ppm (d) relative to internal TMS, and coupling
constants (J) are reported in Hertz (Hz). Melting points
were measured with an Electrotherma1 9100 apparatus.
Elemental analyses for C, H, and N were performed using a
Heraeus CHN–O-Rapid analyzer. The results agreed
favorably with the calculated values. Mass spectra
were recorded with a Shimadzu QP-GC Mass 1100-EX
spectrometer operating at an ionization potential of 70 eV.
IR spectra were measured with Bruker Tensor 27
spectrometer.
(3H, s, CH3CO), 3.74 (1H, m, NCH), 3.67, 3.84 (6H, 2s, 2
OCH3), 6.61 (1H, s, C=CH) ppm; 13C NMR (75.4 MHz,
CDCl3): d = 25.2, 25.4, 26.7, 29.2, 29.8 (5 CH2), 25.4
(CH3CO), 52.3 and 53.0 (2 OCH3), 60.1 (NCH), 122.7
(C=CH), 143.9 (C=CH), 163.2 (NCO), 165.0, 166.7 (2
CO2CH3), 174.2 (CH3CON) ppm; MS: m/z (%) = 311
(M?, 0.4), 170 (3), 155 (3), 86 (17), 84 (40), 60 (35), 43
(100).
Dimethyl 2-(N-acetyl-N-cyclohexylamino)-5-(cyclohexyl-
amino)-3,4-furandicarboxylate (5a, C22H32N2O6)
Yellow oil; 0.04 g (10%); IR (KBr): vꢀ = 3,288 (NH),
1
1,750, 1,712 (C=O), 1,294, 1,170 (C–O) cm-1; H NMR
General procedure
(300 MHz, CDCl3): d = 1.12–2.30 (20H, m, 10 CH2), 3.10
(3H, s, CH3CO), 3.20–3.45 (2H, m, 2 NCH), 3.87, 3.89
(6H, 2s, 2 OCH3), 6.91 (1H, br s, NH) ppm; 13C NMR
(75.4 MHz, CDCl3): d = 23.2, 24.4, 25.1, 25.2, 25.5, 25.5,
26.2, 28.2, 29.8, 30.1, 31.1 (10 CH2, CH3CO), 52.7, 52.9 (2
OCH3), 53.5, 60.9 (2 NCH), 89.2 (furan-C4), 118.2 (furan-
C3), 135.7 (furan-C5), 161.7 (furan-C2), 161.7, 162.4 (2
CO2CH3), 173.2 (C=O) ppm; MS (M? = 420).
To a stirred solution of the anhydride (1 mmol) and dialkyl
acetylenedicarboxylate (1 mmol) in 10 cm3 dichlorometh-
ane was added the isocyanide (2 mmol) in 2 cm3
dichloromethane at room temperature over 10 min via a
syringe. The reaction mixture was stirred at room tem-
perature for 24 h. The solvent was removed under reduced
pressure and the residue was purified by silica gel column
chromatography (Merck silica gel 60, 70–230 mesh) using
hexane–ethyl acetate (8:2) as eluent.
Dimethyl (E)-2-[(N-acetyl-N-tert-butylamino)carbonyl]-2-
butenedioate (4b, C13H19NO6)
Yellow oil; 0.028 g (10%); IR (KBr): vꢀ = 1,710 and 1,685
Dimethyl (E)-2-[(N-acetyl-N-cyclohexylamino)-
carbonyl]-2-butenedioate (4a, C15H21NO6)
1
(C=O), 1,645 (C=C), 1,300 and 1,250 (C–O) cm-1; H
NMR (300 MHz, CDCl3): d = 1.60 (9H, s, NCMe3), 2.12
(3H, s, CH3CO), 3.98, 3.99 (6H, 2s, 2 OCH3), 6.34 (1H, s,
C=CH) ppm; 13C NMR (75.4 MHz, CDCl3): d = 25.4
Pale yellow oil; 0.244 g (78%); IR (KBr): vꢀ = 1,710, 1,685
1
(C=O), 1,645 (C=C), 1,300, 1,250 (C–O) cm-1; H NMR
(300 MHz, CDCl3): d = 1.24–2.20 (10H, m, 5 CH2), 2.39
123

336
M. Bayat et al.
(CH3CO), 28.7 (NCMe3), 52.9, 53.1 (2 OCH3), 123.0
(C=CH), 144.1 (C=CH), 163.3 (NCO), 165.2, 166.7 (2
CO2CH3), 173.8 (CH3CON) ppm; MS (M? = 285).
(OCH2), 128.5 (C=CH), 128.6 (2 CHmeta), 130.6 (2
CHortho), 134.1 (CHpara), 135.9 (Cipso), 141.7 (C=CH),
162.6 (NCO), 162.6, 163.5 (2 CO2Et), 175.2 (PhCON)
ppm; MS: m/z (%) = 375 (M?, 0.2), 122 (21), 105 (44), 77
(100), 52 (86), 39 (28).
Dimethyl 2-(N-acetyl-N-tert-butylamino)-5-(tert-butylami-
no)-3,4-furandicarboxylate (5b, C18H28N2O6)
Yellow powder; 0.296 g (80%); IR (KBr): vꢀ = 3,285
(NH), 1,737, 1,710, 1,651 (C=O), 1,367, 1,296 (C–O)
Dimethyl (E)-2-[(N-benzoyl-N-tert-butylamino)carbonyl]-
2-butenedioate (4e, C18H21NO6)
cm-1 1H NMR (300 MHz, CDCl3): d = 1.36 (9H, s,
;
Pale yellow crystals; m.p.: 130–132 °C; 0.295 g (85%); IR
(KBr): vꢀ = 1,726, 1,689 (C=O), 1,650 (C=C), 1,603,
;
1,585, 1,435 (Ph), 1,210, 1,179 (C–O) cm-1 1H NMR
CMe3), 1.42 (9H, s, CMe3), 1.96 (3H, s, CH3CO), 3.77,
3.84 (6H, 2s, 2 OCH3), 6.90 (1H, br s, NH) ppm; 13C NMR
(75.4 MHz, CDCl3): d = 24.5 (CH3CO), 28.1, 29.7 (2
CMe3), 51.2, 52.3 (2 OCH3), 52.7, 60.2 (2 CMe3), 85.9
(furan-C4), 113.6 (furan-C3), 139.7 (furan-C5), 159.6
(furan-C2), 163.3, 165.1 (2 CO2CH3), 172.5 (C=O) ppm;
MS (M? = 368).
(300 MHz, CDCl3): d = 1.63 (9H, s, CMe3), 3.66, 3.77
(6H, 2s, 2 OCH3), 6.46 (1H, s, C=CH), 7.42 (2H, dd,
3
3JHH = 7.5 Hz, JHH = 7.5 Hz, 2 CHmeta), 7.51 (1H, t,
3
3JHH = 7.4 Hz, CHpara), 7.80 (2H, d, JHH = 7.4 Hz, 2
CHortho) ppm; 13C NMR (75.4 MHz, CDCl3): d = 28.4
(CMe3), 52.5, 52.8 (2 OCH3), 59.9 (CMe3), 128.5 (C=CH),
128.6 (2 CHmeta), 130.6 (2 CHortho), 134.2 (CHpara), 135.8
(Cipso), 141.1 (C=CH), 162.3 (NCO), 163.0, 163.8 (2
CO2Me), 175.2 (PhCON) ppm; MS: m/z (%) = 347 (M?,
0.1), 171 (18), 105 (100), 77 (56), 57 (10), 41 (9).
Di-tert-butyl (E)-2-[(N-acetyl-N-tert-butylamino)-
carbonyl]-2-butenedioate (4c, C19H31NO6)
Pale yellow oil, 0.114 g (30%); IR (KBr): vꢀ = 1,720, 1,691
1
(C=O), 1,658 (C=C), 1,251, 1,245, 1,180 (C–O) cm-1; H
NMR (300 MHz, CDCl3): d = 1.26, 1.49, 1.50 (27H, 3s, 3
CMe3), 2.49 (3H, s, CH3CO), 6.58 (1H, s, C=CH) ppm; 13
C
Dimethyl 2-(N-benzoyl-N-tert-butylamino)-5-(tert-butyl-
amino)-3,4-furandicarboxylate (5e, C23H30N2O6)
NMR (75.4 MHz, CDCl3): d = 25.5 (CH3CO), 27.7, 28.3
(2 CMe3), 28.8 (NCMe3), 60.6 (NCMe3), 82.3, 83.2 (2
CMe3), 122.5 (C=CH), 144.2 (C=CH), 163.2 (NCO),
165.2, 166.7 (2 CO2CMe3), 174.2 (CH3CON) ppm.
Yellow paste; 0.052 g (12%); IR (KBr): vꢀ = 3,328 (NH),
1,730, 1,705, 1,682 (C=O), 1,608 (C=C), 1,251, 1,210
(C–O) cm-1; 1H NMR (300 MHz, CDCl3): d = 1.37, 1.42
(9H, 2s, 2 CMe3), 3.74, 3.79 (6H, 2s, 2 OCH3), 6.90 (1H, s,
Di-tert-butyl
2-(N-acetyl-N-tert-butylamino)-5-(tert-bu-
tylamino)-3,4-furandicarboxylate (5c, C24H40N2O6)
Orange powder, 0.272 g (60%); IR (KBr): vꢀ = 3,350 (NH),
1,732, 1,710, 1,690 (C=O), 1,603 (C=C), 1,367, 1,260
(C–O) cm-1; 1H NMR (300 MHz, CDCl3): d = 1.38, 1.40,
1.52, 1.53 (36H, 4s, 4 CMe3), 1.99 (3H, s, CH3CO), 6.45
(1H, s, NH) ppm; 13C NMR (75.4 MHz, CDCl3): d = 24.4
(CH3CO), 28.2, 28.3, 28.6, 29.8 (4 CMe3), 52.4, 60.0 (2
NCMe3), 80.4, 82.1 (2 OCMe3), 87.6 (furan-C4), 115.5
(furan-C3), 138.3 (furan-C5), 159.2 (furan-C2), 161.8,
164.48 (2 CO2CMe3), 172.9 (C=O) ppm; MS: m/z
(%) = 452 (0.2), 143 (5), 98 (5), 77 (7), 71 (16), 58 (68),
43 (100).
3
3
NH), 7.42 (2H, dd, JHH = 7.3 Hz, JHH = 7.4 Hz, 2
3
CHmeta), 7.60 (1H, t, JHH = 7.3 Hz, CHpara), 7.80 (2H, d,
3JHH = 7.3 Hz, 2 CHortho) ppm; 13C NMR (75.4 MHz,
CDCl3): d = 28.1, 29.7 (2 CMe3), 51.2, 52.3 (2 OCH3),
52.4, 60.3 (2 NCMe3), 85.2 (furan-C4), 114.1 (furan-C3),
128.5 (CHpara), 130.2 (2 CHortho), 133.8 (2 CHmeta), 136.9
(Cipso), 138.1 (furan-C5), 159.0 (furan-C2), 163.3, 164.4 (2
CO2Me), 175.2 (C=O) ppm; MS (M? = 430).
Diethyl 2-(N-acetyl-N-tert-butylamino)-5-(tert-butylami-
no)-3,4-furandicarboxylate (5f, C20H32N2O6)
Colorless crystals; m.p.: 108–110 °C; 0.336 g (85%); IR
(KBr): vꢀ = 3,352 (NH), 1,732, 1,670 (C=O), 1,463
Diethyl (E)-2-[(N-benzoyl-N-tert-butylamino)carbonyl]-2-
butenedioate (4d, C20H25NO6)
1
(C=C), 1,216 (C–O) cm-1; H NMR (300 MHz, CDCl3):
3
d = 1.28 (3H, t, JHH = 7.1 Hz, CH3), 1.29 (3H, t,
Pale yellow powder; m.p.: 115–117 °C; 0.348 g (93%); IR
(KBr): vꢀ = 1,739, 1,722 (C=O), 1,668 (C=C), 1,598, 1,451
3JHH = 7.2 Hz, CH3), 1.36 (9H, s, CMe3), 1.40 (9H, s,
CMe3), 1.96 (3H, s, CH3CO), 4.27 (2H, q,
(Ph), 1,259, 1,174 (C–O) cm-1
;
1H NMR (300 MHz,
3
3JHH = 7.2 Hz, OCH2), 4.41 (2H, q, JHH = 7.1 Hz,
3
CDCl3): d = 1.24 (3H, t, JHH = 7.2 Hz, CH3), 1.28 (3H,
t, JHH = 7.2 Hz, CH3), 1.60 (3H, s, CMe3), 4.10 (2H, q,
OCH2), 6.90 (1H, s, NH) ppm; 13C NMR (75.4 MHz,
CDCl3): d = 14.1, 14.3 (2 CH3CH2), 24.5 (CH3CO),
28.1, 29.7 (2 CMe3), 52.6, 60.2 (2 CMe3), 59.8, 61.4 (2
OCH2CH3), 86.1 (furan-C4), 114.0 (furan-C3), 139.0
(furan-C5), 159.5 (furan-C2), 163.1, 164.7 (2 CO2Et),
172.6 (C=O) ppm; MS: m/z (%) = 143 (35), 125 (8), 98
(15), 81 (16), 56 (39), 53 (57), 43 (100).
3
3JHH = 7.0 Hz, OCH2CH3), 4.20 (2H, q, JHH = 7.0 Hz,
OCH2CH3), 6.40 (1H, s, C=CH), 7.41 (2H, dd,
3
3
3JHH = 7.4 Hz, JHH = 7.5 Hz, 2 CHmeta), 7.56 (1H, t,
3JHH = 7.4 Hz, CHpara), 7.81 (2H, d, JHH = 7.6 Hz, 2
3
CHortho) ppm; 13C NMR (75.4 MHz, CDCl3): d = 13.8,
14.1 (2 CH2CH3), 28.5 (CMe3), 59.8 (CMe3), 61.5, 62.2
123

One-pot three-component condensation reaction
337
Diethyl (E)-2-[(N-benzoyl-N-cyclohexylamino)carbonyl]-
2-butenedioate (4g, C22H27NO6)
Dimethyl (E)-2-[(N-cyclohexyl-N-isobutyrylamino)-
carbonyl]-2-butenedioate (4i, C17H25NO6)
Colorless crystals; m.p.: 114–116 °C; 0.362 g (90%); IR
(KBr): vꢀ = 1,735, 1,690 (C=O), 1,660 (C=C), 1,601, 1,579
Pale yellow paste; 0.264 g (78%); IR (KBr): vꢀ = 1,725,
1
1,700 (C=O), 1,678 (C=C), 1,254, 1,055 (C–O) cm-1; H
(Ph), 1,185, 1,120 (C–O) cm-1
;
1H NMR (300 MHz,
NMR (300 MHz, CDCl3): d = 1.10–1.90 (10H, m, 5 CH2),
3
3
CDCl3): d = 1.30 (3H, t, JHH = 7.2 Hz, CH3), 1.34 (3H,
t, JHH = 7.2 Hz, CH3), 1.83–2.40 (10H, m, 5 CH2), 3.50
1.16 (6H, d, JHH = 6.8 Hz, Me2CH), 2.55 (1H, hept,
3
3JHH = 6.8 Hz, Me2CH), 3.65 (1H, m, NCH), 3.80, 3.92
(6H, 2s, 2 OCH3), 6.55 (1H, s, C=CH) ppm; 13C NMR
(75.4 MHz, CDCl3): d = 19.2 (Me2CH), 23.4, 23.9, 25.4,
26.3, 26.5, 29.3 (5 CH2 and Me2CH), 51.0 (NCH), 51.7,
52.2 (2 OCH3), 122.2 (C=CH), 142.6 (C=CH), 159.7
(NCO), 160.5, 162.1 (2 CO2Me), 171.0 (Me2CHCON)
ppm; MS (M? = 339).
3
(1H, m, NCH), 4.22 (2H, q, JHH = 7.2 Hz, OCH2), 4.28
3
(2H, q, JHH = 7.2 Hz, OCH2), 6.43 (1H, s, C=CH), 7.42
3
3
(2H, dd, JHH = 7.4 Hz, JHH = 7.5 Hz, 2 CHmeta), 7.50
(1H, t, 3JHH = 7.4 Hz, CHpara), 7.80 (2H, d, 3JHH = 7.4 Hz,
2 CHortho) ppm; 13C NMR (75.4 MHz, CDCl3): d = 13.9,
14.0 (2 CH3), 25.2, 26.4, 26.4, 26.4, 29.3 (5 CH2), 60.4, 61.5
(2 OCH2), 62.2 (NCH), 128.5 (2 CHmeta), 128.6 (2 CHortho),
130.6 (C=CH), 134.6 (CHpara), 135.5 (Cipso), 142.7 (C=CH),
162.7 (NCO), 164.3, 165.9 (2 CO2Et), 175.1 (PhCON) ppm;
MS: m/z (%) = 401 (M?, 0.1), 123 (4), 122 (19), 105 (71), 77
(82), 52 (100).
Dimethyl 5-(cyclohexylamino)-2-(N-cyclohexyl-N-isobuty-
rylamino)-3,4-furandicarboxylate (5i, C24H36N2O6)
Yellow oil; 0.045 g (10%); IR (KBr): vꢀ = 3,295 (NH),
1
1,745, 1,720 (C=O), 1,250, 1,170 (C–O) cm-1; H NMR
(300 MHz, CDCl3): d = 1.10–2.30 (26H, m, 10 CH2 and
Me2CH), 2.60 (1H, hept, Me2CH), 3.20–3.45 (2H, m, 2
NCH), 3.81, 3.88 (6H, 2s, 2 OCH3), 6.89 (1H, br s, NH)
ppm; 13C NMR (75.4 MHz, CDCl3): d = 21.8, 23.2, 24.4,
25.1, 25.2, 25.5, 25.5, 26.2, 29.8, 30.1, 31.1 (10 CH2 and
Me2CH), 42.2 (Me2CH), 52.9, 53.3 (2 OCH3), 53.3, 60.4 (2
NCH), 89.5 (furan-C4), 118.4 (furan-C3), 135.6 (furan-C5),
161.7 (furan-C2), 161.7, 162.3 (2 CO2CH3), 173.9 (C=O)
ppm; MS (M? = 448).
Dimethyl (E)-2-[(N-benzoyl-N-cyclohexylamino)carbonyl]-
2-butenedioate (4h, C20H23NO6)
Pale yellow paste; 0.299 g (80%); IR (KBr): vꢀ = 1,741,
1,695 (C=O), 1,658 (C=C), 1,594, 1,460 (Ph), 1,279, 1,150
(C–O) cm-1; 1H NMR (300 MHz, CDCl3): d = 1.51–2.40
(10H, m, 5 CH2), 3.45 (1H, m, NCH), 3.76, 3.82 (6H, 2s, 2
OCH3), 6.55 (1H, s, C=CH), 7.45 (2H, t, 3JHH = 7.6 Hz, 2
3
CHmeta), 7.60 (1H, t, JHH = 7.4 Hz, CHpara), 8.15 (2H, d,
3JHH = 7.5 Hz, 2 CHortho) ppm; 13C NMR (75.4 MHz,
CDCl3): d = 25.4, 26.3, 26.5, 29.3 (5 CH2), 52.4, 53.0 (2
OCH3), 60.4 (NCH), 128.5 (C=CH), 128.6 (2 CHmeta),
130.6 (2 CHortho), 135.3 (CHpara), 135.5 (Cipso), 142.5
(C=CH), 163.2 (NCO), 164.6, 165.8 (2 CO2Me), 175.2
(PhCON) ppm; MS: m/z (%) = 373 (M?, 0.2), 122 (21),
105 (100), 77 (78), 52 (96).
Di-tert-butyl (E)-2-[(N-acetyl-N-cyclohexylamino)-
carbonyl]-2-butenedioate (4j, C21H33NO6)
Liquid oil; 0.316 g (80%), IR (KBr): vꢀ = 1,717, 1,695
1
(C=O), 1,650 (C=C), 1,282, 1,210 (C–O) cm-1; H NMR
(300 MHz, CDCl3): d = 1.12–1.90 (10H, m, 5 CH2), 1.45,
1.50 (18H, 2s, 2 CMe3), 2.41 (3H, s, CH3CO), 3.56 (1H, m,
NCH), 6.54 (1H, s, C=CH) ppm; 13C NMR (75.4 MHz,
CDCl3): d = 25.4 (CH3CO), 24.1, 25.2, 26.4, 26.7, 29.2,
29.3 (5 CH2), 27.8, 27.9 (2 CMe3), 60.4 (NCH), 82.2, 83.2
(2 CMe3), 126.8 (C=CH), 143.7 (C=CH), 161.7 (NCO),
163.6, 167.7 (2 CO2CMe3), 173.9 (CH3CON) ppm; MS:
m/z (%) = 156 (2), 142 (3), 95 (2), 60 (18), 59 (24), 58
(100), 56 (20), 44 (16), 43 (62), 41 (66).
Dimethyl 2-(N-benzoyl-N-cyclohexylamino)-5-(cyclohexyl-
amino)-3,4-furandicarboxylate (5h, C27H34N2O6)
Yellow paste; 0.048 g (10%); IR (KBr): vꢀ = 3,340 (NH),
1
1,730, 1,685 (C=O), 1,600 (C=C), 1,215 (C–O) cm-1; H
NMR (300 MHz, CDCl3): d = 1.10–2.25 (20H, m, 10
CH2), 3.15–3.45 (2H, m, 2 NCH), 3.72, 3.81 (6H, 2s, 2
3
OCH3), 6.80 (1H, br s, NH) 7.44 (2H, t, JHH = 7.6 Hz, 2
3
Diethyl (E)-2-[(N-acetyl-N-cyclohexylamino)carbonyl]-2-
butenedioate (4k, C17H25NO6)
CHmeta), 7.64 (1H, t, JHH = 7.4 Hz, CHpara), 8.10 (2H, d,
3JHH = 7.5 Hz, 2 CHortho) ppm; 13C NMR (75.4 MHz,
CDCl3): d = 23.2, 24.4, 25.1, 25.2, 25.5, 25.5, 26.2, 29.8,
30.1, 31.1 (10 CH2), 52.7, 53.1 (2 OCH3), 53.6, 60.9 (2
NCH), 88.7 (furan-C4), 114.7 (furan-C3), 130.1 (CHpara),
130.2 (2 CHortho), 133.8 (2 CHmeta), 135.7 (furan-C5),
136.9 (Cipso), 159.9 (furan-C2), 161.8, 162.6 (2 CO2CH3),
173.2 (C=O) ppm; MS: m/z (%) = 143 (4), 122 (22), 105
(54), 77 (100), 76 (22), 53 (18), 52 (96).
Yellow oil; 0.169 g (50%); IR (KBr): vꢀ = 1,726, 1,684
1
(C=O), 1,643 (C=C), 1,305, 1,250 (C–O) cm-1; H NMR
(300 MHz, CDCl3): d = 1.20–1.95 (10H, m, 5 CH2), 1.23,
1.26 (6H, 2t, 2 CH3) 2.34 (3H, s, CH3CO), 3.65 (1H, m,
3
NCH), 4.17, 4.22 (4H, 2q, JHH = 7.2 Hz, 2 OCH2), 6.56
(1H, s, C=CH) ppm; 13C NMR (75.4 MHz, CDCl3):
d = 13.9, 14.1 (2 CH3), 25.2, 25.4, 25.4, 26.4, 29.3,
123

338
M. Bayat et al.
¨
6. Domling A (2006) Chem Rev 106:17
7. Banfi L, Riva R (2005) Org React 65:1
29.85 (5 CH2 and CH3CO), 60.4 (NCH), 61.4, 62.2 (2
OCH2), 123.6 (C=CH), 142.7 (C=CH), 162.7 (NCO),
164.3, 165.9 (2 CO2Et), 175.1 (CH3CON) ppm; MS: m/z
(%) = 339 (M?, 0.2), 170 (8), 143 (16), 98 (14), 69 (13),
67 (16), 60 (28), 56 (48), 53 (100).
¨
8. Domling A, Ugi I (2000) Angew Chem Int Ed 39:3168
¨
9. Domling A (2000) Curr Opin Chem Biol 4:318
10. Tietze LF, Modi A (2000) Med Res Rev 20:304
11. Orru RVA, de Greef M (2003) Synthesis 1471
12. Zhu J (2003) Eur J Org Chem 1133
Diethyl 2-(N-acetyl-N-cyclohexylamino)-5-(cyclohexyl-
amino)-3,4-furandicarboxylate (5k, C24H36N2O6)
¨
13. Ugi I, Domling A, Werner B (2000) J Heterocycl Chem 37:647
14. Ugi I, Werner B, Domling A (2000) Targets Heterocycl Syst 4:1
15. Lipshutz BH (1986) Chem Rev 86:795
16. Nakanishi K (1974) Natural products chemistry. Kodansha,
Tokyo
¨
Yellow paste; 0.112 g (25%); IR (KBr): vꢀ = 3,235 (NH),
1
1,742, 1,723 (C=O), 1,244, 1,167 (C–O) cm-1; H NMR
(300 MHz, CDCl3): d = 1.12–2.30 (26H, m, 10 CH2 and 2
CH3), 3.14 (3H, s, CH3CO), 3.15–3.40 (2H, m, 2 NCH),
17. Yadav JS, Subba Reddy BV, Shubashree S, Sadashiv K, Krishna
Rao D (2007) J Mol Catal A: Chemical 272:128
18. Esmaili AA, Bodaghi A (2003) Tetrahedron 59:1169
19. Shaabani A, Teimouri MB, Bijanzadeh HR (2002) J Chem Res
(S) 381
20. Nair V, Rajeev SM, Ani D, Rema D, Biju AT (2005) Tetrahedron
Lett 46:1337
21. Yavari I, Mokhtarporyani-Sanandaj A, Moradi L, Mirzaei A
(2008) Tetrahedron 64:5221
22. Teimouri MB, Shaabani A, Bazhrang R (2004) Tetrahedron
62:1845
23. Nair V, Vinod AU, Nair JS, Sreekanth AR, Rath NP (2000)
Tetrahedron Lett 41:6675
3
4.23 (2H, q, JHH = 7.4 Hz, OCH2), 4.45 (2H, q,
3JHH = 7.4 Hz, OCH2), 6.92 (1H, br s, NH) ppm; 13C
NMR (75.4 MHz, CDCl3): d = 14.2, 14.3 (2 CH3), 23.2,
24.4, 25.1, 25.2, 25.5, 25.5, 26.2, 28.1, 29.8, 30.1, 31.1 (10
CH2 and CH3CO), 53.5, 60.9 (2 NCH), 59.7, 61.2 (2
OCH2), 86.2 (furan-C4), 114.1 (furan-C3), 139.2 (furan-
C5), 159.5 (furan-C2), 162.9, 163.8 (2 CO2CH3), 172.6
(C=O) ppm; MS (M? = 448).
24. Shaabani A, Teimouri MB, Arab-Ameri S (2004) Tetrahedron
Lett 45:8409
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123