Competition of the R3P/DAAD and RNC/DAAD zwitterions in their production and reaction with aromatic carboxylic acids: A novel binucleophilic system for three-component synthesis of 2-aminofurans

Article abstract of DOI:10.1055/s-2008-1067028

We recently reported a new class of triphenylphosphine and isocyanide based multicomponent reactions (Ph₃P/DAAD and IMCRs/DAAD) mediated by R₃P/DAAD and RNC/DAAD zwitterionic intermediates in the presence of CH, OH, and NH acids. Her

Full text of DOI:10.1055/s-2008-1067028

1788
PAPER
Competition of the R3P/DAAD and RNC/DAAD Zwitterions in Their
Production and Reaction with Aromatic Carboxylic Acids: A Novel
Binucleophilic System for Three-Component Synthesis of 2-Aminofurans
T
hree-Component
b
Synthesis of
d
2-Aminofur
o
ans lali Alizadeh,*a Sadegh Rostamnia,a Long-Guan Zhub
a
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran 18716, Iran
Fax +98(21)88006544; E-mail: aalizadeh@modares.ac.ir
Chemistry Department, Zhejiang University, Hangzhou 310027, P. R. of China
b
Received 13 February 2008; revised 27 February 2008
It was of interest to compare and investigate the reactivity
of the Ph3P/DAAD and RNC/DAAD zwitterions towards
carboxylic acids. The present studies were initiated by
triphenylphosphine and tert-butyl isocyanide as nucleo-
Abstract: We recently reported a new class of triphenylphosphine
and isocyanide based multicomponent reactions (Ph3P/DAAD and
IMCRs/DAAD) mediated by R3P/DAAD and RNC/DAAD zwitter-
ionic intermediates in the presence of CH, OH, and NH acids.
Herein, the reactions of Huisgen 1:1 zwitterionic intermediates, philes, dimethyl acetylenedicarboxylate as the activated
generated from dialkyl acetylenedicarboxylates (DAAD), trivalent
acetylene, and benzoic acid as an initial proton source. In
phosphorus reagents, and isocyanides, with aromatic carboxylic ac-
a pilot experiment, a solution of phosphine or phosphite,
ids as initial proton source are investigated. This novel binucleo-
isocyanide, and aromatic carboxylic acid in anhydrous
philic (R3P–RNC/DAAD) system afforded 2-aminofuran
dichloromethane was treated with an equimolar quantity
derivatives.
of dialkyl acetylenedicarboxylate at room temperature. To
Key words: isocyanide, trialkyl phosphine, trialkyl phosphite, di-
our surprise, in a one-pot reaction between triphenylphos-
alkyl acetylenedicarboxylate, aromatic carboxylic acid, multicom-
phine, tert-butyl isocyanide, and dimethyl acetylenedicar-
boxylate in the presence of benzoic acid, the product was
ponent reaction, aminofuran
dimethyl 2-(tert-butylamino)-5-phenylfuran-3,4-dicar-
boxylate; triphenylphosphine oxide was also isolated
In 1962, Johnson and Tebby established the reaction of
triphenylphosphine with dimethyl acetylenedicarboxy-
from the reaction mixture (Scheme 2).6
late.1 This early finding forms the basis for the synthesis
of a large class of new backbones which are thus accessi-
ble. The chemistry is based upon the initial formation of a
zwitterionic adduct of the phosphine with the acetylene
compounds.2 In the other hand, in 1969, Winterfeldt et al.
described the reaction of isocyanides and acetylenic com-
pounds.3 Recently, we have explored the reactivity of
zwitterions derived from electron-deficient acetylenes
and nucleophiles, such as triphenylphosphine (Ph3P/
DAAD), and isocyanides (RNC/DAAD); these studies
have lead to a number of interesting carbon–carbon and
carbon–heteroatom bond forming reactions and heterocy-
clic syntheses.4
To realize our goal and test the generality of this proce-
dure in the synthesis of 2-aminofurans, we examined this
reaction following different pathways. In all cases, under
the various conditions, the product of these reactions was
the 2-aminofuran, similar to our previous results.
Subsequently, a detailed study of the reaction of other ter-
tiary phosphine and tertiary phosphite reagents, isocya-
nides, and electron-deficient acetylenes with aromatic
carboxylic acids was undertaken and the results are pre-
sented in this paper.
In comparing the generation of Ph3P/DAAD and RNC/
DAAD zwitterions, our investigations were initiated with
triphenylphosphine as the aromatic trivalent phosphine,
isocyanides on treatment with dialkyl acetylenedicarbox-
ylate in the presence of a stoichiometric amount of a ben-
zoic acid derivative, to trap the in situ generated
zwitterion, in dichloromethane afforded a product charac-
terized as the dialkyl 2-(alkylamino)-5-arylfuran-3,4-di-
carboxylate 4 in 69–88% yield (Table 1).
In our recent investigations, the treatment of benzoic acid
and its derivatives with dialkyl acetylenedicarboxylate
and alkyl isocyanide (RNC/DAAD), in anhydrous dichlo-
romethane at room temperature lead to the formation of
linear imide derivatives (Scheme 1).5
CO2R2
O
O
CO2R2
The structures of compounds 4a–g were deduced from
O
CH2Cl2
1
their elemental analysis, IR, and high-field H and 13C
R1
+
N C:
+
H
Ar
N
Ar
OH
r.t., 48 h
NMR spectra. The mass spectrum of 4a displayed the mo-
lecular ion (M+) peak at m/z = 376, which is consistent
with the structure of dimethyl 2-(tert-butylamino)-5-(4-
nitrophenyl)furan-3,4-dicarboxylate structure. The IR
spectrum of 4a exhibited absorption bands due to the car-
bonyl group of esters and ketones at 1724 and 1669 cm–1,
CO2R2
R1
CO2R2
Scheme 1
SYNTHESIS 2008, No. 11, pp 1788–1792
x
x.
x
x
.
2
0
0
8
Advanced online publication: 16.04.2008
DOI: 10.1055/s-2008-1067028; Art ID: Z04208SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Scheme 2
Three-Component Synthesis of 2-Aminofurans
1789
CO2R2
CO2R2
R2O2C
R1
CO2R2
O
Ph3P
R1
N
C
+
Ph3P=O
+
+
Ar
OH
CH2Cl2, r.t.
N
Ar
O
H
Table 1 Reactions of Ph3P–RNC/DAAD Zwitterions with Aro-
matic Carboxylic Acids
Ph3P
R1O2C
CO2R1
R1
1
R1
O
O
O
+
O
24 h
O
Ph3P=O
+
OH
H
CH2Cl2, r.t.
N
R3
R2
O
2
+
R2
4
R3
N C
Figure 1 ORTEP plot of 4a showing the atom numbering scheme
3
4
R1
R2
R3
Yield (%) of 4
Although the mechanistic details of the reaction are not
clearly known, the rationalization presented earlier may
also be invoked here. It is conceivable that the initially
formed zwitterion from triphenylphosphine and dialkyl
acetylenedicarboxylate is protonated by the carboxylic
acid to furnish the vinylphosphoranyl arenecarboxylate
intermediate 5. The latter then eliminates triphenylphos-
phine oxide, the final product 4 is produced by a [4+1] at-
tachment of isocyanide and then aromatization by [1,3] H-
migration (Scheme 3).
4a
4b
4c
4d
4e
4f
Me
Me
Me
Me
Et
NO2
H
t-Bu
t-Bu
Cy
74
69
70
84
88
86
72
H
NO2
NO2
H
Cy
Cy
Et
Cy
In view of the interesting results obtained with triphe-
nylphosphine, the studies were extended using tribu-
tylphosphine. As expected, the reaction of dimethyl
acetylenedicarboxylate with tributylphosphine and tert-
butyl isocyanide in the presence of stoichiometric amount
of 4-nitrobenzoic acid in anhydrous dichloromethane at
room temperature afforded dimethyl 2-(tert-butylamino)-
5-(4-nitrophenyl)furan-3,4-dicarboxylate (4a) as an or-
ange crystalline solid in 85% yield, likewise aminofurans
4b–g were formed in 83–93% yield (Table 2).
4g
Et
NO2
t-Bu
and an NH group at 3445 cm–1, the absorption bands of the
nitro moiety appeared at 1591 and 1326 cm–1.
1
The H NMR spectrum of 4a exhibited four single sharp
lines readily recognized as arising from the tert-butyl
group (d = 1.52), methoxy (d = 3.79 and 3.96) and NH
group (d = 6.97) protons. The phenyl moiety gave rise to
characteristic signals in the aromatic region of the spec-
trum. The 1H decoupled 13C NMR spectrum of 4a showed
14 distinct resonances in agreement with the structure of
dimethyl 2-(tert-butylamino)-5-(4-nitrophenyl)furan-3,4-
dicarboxylate. The structure of compound 4a was con-
firmed by single crystal X-ray analysis (Figure 1).
Based on the interesting chemistry and different nucleo-
philicity of phosphites in comparison with phosphines, we
also used the (RO)3P–RNC/DAAD system. The studies
were extended using phosphites and isocyanides in a binu-
cleophilic system as the initial nucleophile in multicom-
O
R1O2C
Ph3P
CO2R1
R1O2C
R1O2C
Ph3P
CO2R1
2
Ph3P
1
+
Ar
O
H
CO2R1
R1O2C
R1O2C
CO2R1
CO2R1
Ar
[4+1]
3
4
– Ph3P=O
Ar
N
Ph3P
O
O
O
C
R3
N
Ar
O
R3
5
Scheme 3
Synthesis 2008, No. 11, 1788–1792 © Thieme Stuttgart · New York

1790
A. Alizadeh et al.
PAPER
Table 2 Reaction of the Bu3P–RNC/DAAD Zwitterions with Ben-
zoic Acid Derivatives
lenedicarboxylate in the presence of benzoic acid deriva-
tives afforded dialkyl 2-(alkylamino)-5-arylfuran-3,4-
dicarboxylate 4 shows that the nucleophilicity of phos-
phites is more than that of the isocyanides and the first
zwitterionic adduct results from the reaction of the phos-
phite and the acetylenic compound.
R1O
CO2R1
R1O2C
O
CH2Cl2
H
Ar CO2H
R2
N C
Bu3P
+
+
+
N
r.t.
Ar
O
4
R2
CO2R1
It is conceivable that the products 4 are important structur-
al fragments in organic synthesis. Substituted furans play
an important role in organic chemistry, not only as key
structural units in many natural products and important
pharmaceuticals,7 but also as useful building blocks in
synthetic chemistry.8 While many synthetic routes exist
for the synthesis of furans, convergent annulation strate-
gies without transition-metal catalysis are uncommon.9,10
4
R1
R2
Ar
Yield (%) of 4
4a
4b
4c
4d
4e
4f
Me
Me
Me
Me
Et
t-Bu
t-Bu
Cy
4-O2NC6H4
Ph
85
76
83
91
91
88
93
Ph
Cy
4-O2NC6H4
4-O2NC6H4
Ph
In this context it is interesting to note that only a few re-
ports involving one-pot multicomponent reactions with
two different nucleophilic addition are available in the lit-
erature.11–13
Cy
Et
Cy
4g
Et
t-Bu
4-O2NC6H4
In summary, we have shown that R3P/DAAD and RNC/
DAAD zwitterions from the reaction of dialkyl acetylene-
dicarboxylate, phosphines or phosphites, and isocyanides
on reaction with aromatic carboxylic acids as the initial
proton source afforded 2-aminofuran derivatives, which
showed that the first zwitterion formed was from trivalent
phosphorus and dialkyl acetylenedicarboxylates.
ponent conditions. The reaction was also found to work
well with other trivalent phosphorus reagents such as
phosphines; the results are summarized in Table 3. Inter-
estingly, the reaction between trialkyl or triaryl phosphites
and isocyanides, which on treatment with dialkyl acety-
Table 3 Reaction of (RO)3P–DAAD Zwitterions with Benzoic Acid Derivatives in the Presence of Isocyanides
OR2
CO2R2
R2O2C
CO2R2
CO2H
R1
N C
O
CH2Cl2
r.t.
H
N
R1
+
(R4O)3P
R3
O
R3
4
4
R1
R2
R3
(R4O)3P
Yield (%) of 4
4a
4b
4c
4d
4e
4f
t-Bu
t-Bu
Cy
Me
Me
Me
Me
Et
NO2
(MeO)3P
(EtO)3P
(PhO)3P
74
76
80
H
(MeO)3P
(EtO)3P
(PhO)3P
80
83
80
H
(MeO)3P
(EtO)3P
(PhO)3P
78
80
87
Cy
NO2
NO2
H
(MeO)3P
(EtO)3P
(PhO)3P
84
85
89
Cy
(MeO)3P
(EtO)3P
(PhO)3P
88
85
91
Cy
Et
(MeO)3P
(EtO)3P
(PhO)3P
74
76
82
4g
t-Bu
Et
NO2
(MeO)3P
(EtO)3P
(PhO)3P
84
89
91
Synthesis 2008, No. 11, 1788–1792 © Thieme Stuttgart · New York

PAPER
Three-Component Synthesis of 2-Aminofurans
1791
(C4furan), 124.55 (2 CHPh), 128.74 (2 CHPh), 129.60 (CHPh), 134.91
(Cipso), 141.31 (C5furan), 161.61 (C2furan), 165.03 (CO2Me), 166.10
(CO2Me).
MS: m/z (%) = 349 (M+ + H2O, 3), 332 (M+ + 1, 4), 304 (5), 275 (7),
Dimethyl and diethyl acetylenedicarboxylates and tert-butyl and
cyclohexyl isocyanides were obtained from Merck (Germany) and
Fluka (Switzerland) and were used without further purification.
Melting points were measured on an Electrothermal 9100 appara-
tus. Elemental analyses for C, H and N were performed using a Her-
aeus CHN–O–Rapid analyzer. Mass spectra were recorded on a
FINNIGAN-MATT 8430 mass spectrometer operating at an ioniza-
150 (18), 105 (100), 91 (5), 77 (34), 43 (12), 41 (28).
Anal. Calcd for C18H21NO5 (331.37): C, 65.24; H, 6.39; N, 4.23.
Found: C, 65.50; H, 6.42; N, 4.30.
1
tion potential of 20 eV. H and 13C NMR spectra were measured
(CDCl3) with a Bruker DRX-500 AVANCE spectrometer at 500.13
and 125.8 MHz, respectively. IR spectra were recorded on a Shi-
madzu IR-460 spectrophotometer. Chromatography columns were
prepared from Merck silica gel 230–240 mesh.
Dimethyl 2-(Cyclohexylamino)-5-phenylfuran-3,4-dicarboxy-
late (4c)
Viscous pale yellow oil.
IR (KBr): 3325 (NH), 1708 (CO2Me), 1678 (CO2Me), 1555 and
1480 (Ph), 1250, 1259, 1197, 1100 and 1050 (C–O) cm–1.
1H NMR (500.1 MHz, CDCl3): d = 1.14-2.34 (m, 10 H, 5 CH2 of c-
Hex), 3.72 (m, 1 H, NCH), 3.76 (s, 3 H, OMe), 3.82 (s, 3 H, OMe),
7.15 (t, J = 7.4 Hz, 1 H, NH), 7.44 (t, J = 7.8 Hz, 1 H, CHPh), 7.53
(t, J = 7.4 Hz, 2 H, 2 CHPh), 7.64 (d, J = 7.1 Hz, 2 H, 2 CHPh).
13C NMR (125.7 MHz, CDCl3): d = 25.16–29.28 (5 CH2 of c-Hex),
52.34 (CHN ), 52.98 (OMe), 60.39 (OMe), 93.00 (C3furan), 113.00
(C4furan), 128.42 (2 o-CHPh), 128.57 (2 m-CHPh), 132.56 (p-CHPh),
135.27 (Cipso), 142.44 (C5furan), 163.13 (C2furan), 164.57 (CO2Me),
165.73 (CO2Me).
Dimethyl 2-(tert-Butylamino)-5-(4-nitrophenyl)furan-3,4-di-
carboxylate (4a); Typical Procedure Using Triphenylphosphine
To a magnetically stirred soln of 4-nitrobenzoic acid (0.17 g, 1
mmol) and DMAD (0.14 g, 1 mmol) in anhyd CH2Cl2 (5 mL) was
added dropwise a soln mixture of Ph3P (0.26 g, 1 mmol) and tert-
butyl isocyanide (0.83 g, 1 mmol) in anhyd CH2Cl2 (3 mL) at r.t.
over 20 min; the mixture was stirred for 24 h. The solvent was re-
moved under reduced pressure and the residue was separated by
column chromatography (silica gel, Merck 230–240 mesh, hexane–
EtOAc) to give 4a as orange crystals; yield: 0.28 g (74%); mp 177–
179 °C.
MS: m/z (%) = 374 (M+ + H2O, 1), 348 (2), 314 (3), 232 (5), 150 (3),
122 (12), 105 (39), 77 (18), 58 (34), 43 (100), 41 (9).
IR (KBr): 3445 (NH), 1724 (CO2Me), 1669 (CO2Me), 1504 and
1468 (Ar), 1591 and 1326 (NO2), 1261, 1213, 1184 and 1103 (C–
O) cm–1.
1H NMR (500.1 MHz, CDCl3): d = 1.52 [s, 9 H, C(CH3)3], 3.79 (s,
3 H, OMe), 3.96 (s, 3 H, OMe), 6.97 (s, 1 H, NH), 7.61 (d, J = 8.9
Hz, 2 H, 2 CHaryl), 8.22 (d, J = 8.9 Hz, 2 H, 2 CHaryl).
13C NMR (125.7 MHz, CDCl3): d = 29.81 [C(CH3)3], 51.43
[C(CH3)3], 53.03 (OMe), 53.13 (OMe), 89.65 (C3furan), 117.51
(C4furan), 123.95 (2 CHaryl), 124.40 (2 CHaryl), 134.99 (Cipso), 138.36
(Cipso-NO2), 146.00 (C5furan), 161.94 (C2furan), 164.58 (CO2Me),
165.50 (CO2Me).
Anal. Calcd for C20H23NO5 (357.40): C, 67.21; H, 6.49; N, 3.92.
Found: C, 67.50; H, 6.50; N, 4.10.
Dimethyl 2-(Cyclohexylamino)-5-(4-nitrophenyl)furan-3,4-di-
carboxylate (4d)
Orange crystals; mp 140–142 °C.
IR (KBr) : 3340 (NH), 1724 (CO2Me), 1671 (CO2Me), 1504 and
1469 (Ar), 1588 and 1327 (NO2), 1256, 1224, 1103 and 1072 (C–
O) cm–1.
1H NMR (500.1 MHz, CDCl3): d = 1.10–2.06 (m, 10 H, 5 CH2 of c-
Hex), 3.77 (m, 1 H, H of c-Hex), 3.78 (s, 3 H, OMe), 3.94 (s, 3 H,
OMe), 6.72 (d, J = 8.0 Hz, 1 H, NH), 7.59 (d, J = 8.9 Hz, 2 H, 2
CHaryl), 8.19 (d, J = 8.9 Hz, 2 H, 2 CHaryl).
13C NMR (125.7 MHz, CDCl3): d = 24.45–33.35 (5 CH2 of c-Hex),
51.31 (CHN), 51.69 (OMe), 52.90 (OMe), 88.81 (C3furan), 117.83
(C4furan), 123.97 (2 CHaryl), 124.24 (2 CHaryl), 134.96 (Cipso), 137.94
(Cipso-NO2), 145.97 (C5furan), 161.57 (C2furan), 164.38 (CO2Me),
165.32 (CO2Me).
MS: m/z (%) = 377 (M+ + 1, 10), 376 (M+, 30), 320 (100), 288 (78),
256 (19), 151 (71), 104 (35), 76 (21), 57 (81), 41 (66).
Anal. Calcd for C18H20N2O7 (376.36): C, 57.44; H, 5.36; N, 7.44.
Found: C, 58.00; H, 5.51; N, 7.52.
Crystal data for 4a: C18H20N2O7 (652092); MW = 376.36, triclinic,
space group P–1, a = 9.2280(13) Å, b = 10.1177(14) Å,
c = 10.9028(15) Å, a = 91.030(2), b = 113.853(2), g = 92.379(2)°,
V = 929.5(2) Å3, Z = 2, Dc = 1.345 mg/m3, F(000) = 396, crystal
dimension 0.11 × 0.15 × 0.21 mm, radiation, MoKa (l = 0.71073
Å), 2.04 £ 2q £ 25.20, intensity data were collected at 295 K with a
Bruker APEX area-detector diffractometer, and employing w/2q
scanning technique, in the range of –11 £ h £ 8, –12 £ k £ 12, –13 £
l £ 13; the structure was solved by a direct method, all non-hydrogen
atoms were positioned and anisotropic thermal parameters refined
from 2415 observed reflections with R(int) = 0.0156 by a full-
matrix least-squares technique converged to R = 0.0475 and
Rw = 0.1227 [I > 2s(I)].
MS: m/z (%) = 402 (M+, 2), 349 (7), 150 (23), 105 (53), 77 (26), 57
(32), 43 (100), 41 (40).
Anal. Calcd for C20H22N2O7 (402.40): C, 59.70; H, 5.51; N, 6.96.
Found: C, 60.00; H, 5.60; N, 7.00.
Diethyl 2-(Cyclohexylamino)-5-(4-nitrophenyl)furan-3,4-dicar-
boxylate (4e)
Orange crystals; mp 137–139 °C.
IR (KBr): 3415 (NH), 1715 (CO2Et), 1669 (CO2Et), 1501 and 1470
(Ar), 1588 and 1327 (NO2), 1225, 1183, 1103 and 1067 (C–O) cm–1.
Dimethyl 2-(tert-Butylamino)-5-phenylfuran-3,4-dicarboxylate
(4b)
1H NMR (500.1 MHz, CDCl3): d = 1.31 (t, J = 7.1 Hz, 3 H,
OCH2CH3), 1.37 (t, J = 7.1 Hz, 3 H, OCH2CH3) 1.41–2.05 (m, 10
H, 5 CH2 of c-Hex), 3.75 (m, 1 H, CHN), 4.24 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 4.41 (t, J = 7.1 Hz, 2 H, OCH2CH3), 6.77 (d, J = 7.9 Hz,
1 H, NH), 7.60 (d, J = 9.0 Hz, 2 H, 2 CHaryl), 8.20 (d, J = 9.0 Hz, 2
H, 2 CHaryl).
13C NMR (125.7 MHz, CDCl3): d = 14.05 (OCH2CH3), 14.38
(OCH2CH3), 24.47–33.39 (5 CH2 of c-Hex), 51.66 (CHN), 59.99
(OCH2CH3), 62.11 (OCH2CH3), 89.60 (C3furan), 118.36 (C4furan),
Colorless crystals; mp 75–77 °C.
IR (KBr): 3380 (NH), 1745 (CO2Me), 1687 (CO2Me), 1514 and
1437 (Ph), 1259, 1212, 1093 and 1071 (C–O) cm–1.
1H NMR (500.1 MHz, CDCl3): d = 1.49 [s, 9 H, C(CH3)3], 3.77 (s,
3 H, OMe), 3.91 (s, 3 H, OMe), 6.81 (s, 1 H, NH), 7.26 (t, J = 7.0
Hz, 1 H, CHPh), 7.37 (t, J = 7.6 Hz, 2 H, 2 CHPh), 7.52 (t, J = 7.5 Hz,
2 H, 2 CHPh).
13C NMR (125.7 MHz, CDCl3): d = 29.90 [C(CH3)3], 51.13
[C(CH3)3], 52.62 (OMe), 53.54 (OMe), 88.52 (C3furan), 113.16
123.84 (2 CHaryl), 124.29 (2 CHaryl), 135.15 (Cipso), 137.63 (Cipso
-
Synthesis 2008, No. 11, 1788–1792 © Thieme Stuttgart · New York

1792
A. Alizadeh et al.
PAPER
NO2), 145.89 (C5furan), 161.67 (C2furan), 164.16 (CO2Et), 164.94
(CO2Et).
(2) Nair, V.; Menon, R. S.; Sreekanth, A. R.; Abhilash, N.; Biju,
A. T. Acc. Chem. Res. 2006, 39, 520.
(3) Winterfeldt, E.; Schumann, D.; Dillinger, H. J. Chem. Ber.
1969, 102, 1656.
MS: m/z (%) = 432 (M+ + 2, 7), 431 (M+ + 1, 29), 430 (M+, 98), 401
(5), 348 (25), 302 (27), 274 (46), 219 (28), 150 (87), 104 (38), 92
(10), 55 (100), 43 (15), 41 (64).
(4) (a) Alizadeh, A.; Masrouri, H.; Rostamnia, S.; Movahedi, F.
Helv. Chim. Acta 2006, 89, 923. (b) Alizadeh, A.;
Rostamnia, S.; Hu, M. L. Synlett 2006, 1592. (c) Alizadeh,
A.; Rostamnia, S.; Esmaili, A. A. Synthesis 2007, 709.
(d) Alizadeh, A.; Oskueyan, Q.; Rostamnia, S. Synthesis
2007, 2637. (e) Alizadeh, A.; Zohreh, N.; Rostamnia, S.
Tetrahedron 2007, 63, 8083. (f)Alizadeh, A.;Rostamnia, S.
Synthesis 2008, 57. (g) Alizadeh, A.; Rostamnia, S.; Zohreh,
N.; Bijanzadeh, H. R. Monatsh. Chem. 2008, 139, 49.
(5) Alizadeh, A.; Rostamnia, S.; Zhu, L. G. Tetrahedron 2006,
62, 5641.
Anal. Calcd for C22H26N2O7 (430.45): C, 61.39; H, 6.09; N, 6.51.
Found: C, 61.40; H, 6.10.; N, 6.70.
Diethyl 2-(Cyclohexylamino)-5-phenylfuran-3,4-dicarboxylate
(4f)
Viscous pale yellow oil.
IR (KBr): 3340 (NH), 1730 (CO2Et), 1670 (CO2Et), 1588 and 1501
(Ph), 1333, 1257, 1191, and 1025 (C–O) cm–1.
1H NMR (500.1 MHz, CDCl3): d = 1.16–1.96 (m, 10 H, 5 CH2 of c-
Hex), 1.26 (t, J = 7.1 Hz, 3 H, OCH2CH3), 1.30 (t, J = 7.0 Hz, 3 H,
OCH2CH3), 3.12 (m, 1 H, CHN ), 4.20 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 3.82 (q, J = 7.0 Hz, 2 H, OCH2CH3), 6.62 (d, J = 7.4
Hz, 1 H, NH), 7.42 (t, J = 7.7 Hz, 1 H, CHPh), 7.52 (t, J = 7.6 Hz, 2
H, 2 CHPh), 7.64 (d, J = 7.3 Hz, 2 H, 2 CHPh).
13C NMR (125.7 MHz, CDCl3): d = 13.91 (OCH2CH3), 14.02
(OCH2CH3), 24.90–30.52 (5 CH2 of c-Hex), 60.31 (CHN), 61.38
(OCH2CH3), 62.14 (OCH2CH3), 96.02 (C3furan), 114.00 (C4furan),
128.41 (2 CHPh), 128.51 (2 CHaryl), 132.48 (CHPh), 135.43 (Cipso),
142.63 (C5furan), 162.61 (C2furan), 164.18 (CO2Et), 165.69 (CO2Et).
(6) Alizadeh, A.; Rostamnia, S.; Zohreh, N.; Oskueyan, Q.
Synlett 2007, 1610.
(7) (a) Dean, F. A. Naturally Occurring Oxygen Ring
Compounds; Butterworth: London, 1963. (b) Natural
Products Chemistry, Vols. 1-3; Nakanishi, K.; Goto, T.; Ito,
S.; Natori, S.; Nozoe, S., Eds.; Kodansha: Tokyo, 1974.
(c) Mortensen, D. S.; Rodriguez, A. L.; Carlson, K. E.; Sun,
J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med.
Chem. 2001, 44, 3838. (d) Bock, I.; Bornowski, H.; Ranft,
A.; Theis, H. Tetrahedron 1990, 46, 1199.
(8) (a) Lipshutz, B. H. Chem. Rev. 1986, 86, 795. (b) Raczko,
J.; Jurcak, J. Stud. Nat. Prod. Chem. 1995, 16, 639.
(9) (a) Cacchi, S. J. Organomet. Chem. 1999, 576, 42. (b)Hou,
X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.;
Tong, S. Y.; Wong, H. N. C. Tetrahedron 1998, 54, 1955.
(10) For the synthesis of furans from acyclic precursors, see:
(a) Nair, V.; Vinod, A. U. Chem. Commun. 2000, 1019.
(b) Jung, C.-K.; Wang, J. C.; Krische, M. J. J. Am. Chem.
Soc. 2004, 126, 4118. (c) Lee, C. F.; Yang, L. M.; Hwu, T.
Y.; Feng, A. S.; Tseng, J. C.; Luh, T. Y. J. Am. Chem. Soc.
2000, 122, 4992. (d) Sromek, A. W.; Kel’in, A. V.;
Gevorgyan, V. Angew. Chem. Int. Ed. 2004, 43, 2280.
(e) Ma, S. M.; Zhang, J. L. J. Am. Chem. Soc. 2003, 125,
12386. (f) Yao, T.-L.; Zhang, X. X.; Larock, R. C. J. Am.
Chem. Soc. 2004, 126, 11164. (g) Marshall, J. A.; Bennett,
C. E. J. Org. Chem. 1994, 59, 6110. (h) Marshall, J. A.;
Wang, X. j. J. Org. Chem. 1991, 56, 960. (i) Méndez-
Andino, J.; Paquette, L. A. Org. Lett. 2000, 2, 4095. (j)Liu,
Y.; Reitman, M.; Zhang, Y.; Fathi, R.; Yang, Z. Org. Lett.
2002, 4, 2607. (k) Redman, A. M.; Dumas, J.; Scoyy, W. J.
Org. Lett. 2000, 2, 2061. (l) Nakamura, M.; Liang, C.;
Nakamura, E. Org. Lett. 2004, 6, 2015.
MS: m/z (%) = 402 (M+ + H2O, 3), 385 (M+, 2), 356 (2), 355 (3), 328
(12), 246 (17), 143 (13), 105 (100), 77 (30), 55 (10), 43 (7), 41 (7).
Anal. Calcd for C22H27NO5 (385.46): C, 68.55; H, 7.06; N, 3.63.
Found: C, 69.00; H, 7.05; N, 3.75.
Diethyl 2-(tert-Butylamino)-5-(4-nitrophenyl)furan-3,4-dicar-
boxylate (4g)
Orange viscous liquid.
IR (KBr): 3325 (NH), 1725 (CO2Et), 1669 (CO2Et), 1513 and 1459
(Ar), 1589 and 1332 (NO2), 1259, 1206, 1091 and 1035 (C–O) cm–1.
1H NMR (500.1 MHz, CDCl3): d = 1.31 (t, J = 7.1 Hz, 3 H,
OCH2CH3), 1.40 (t, J = 7.2 Hz, 3 H, OCH2CH3), 1.56 [s, 9 H,
C(CH3)3], 4.25 (t, J = 7.1 Hz, 2 H, OCH2CH3), 4.42 (t, J = 7.2 Hz,
2 H, OCH2CH3), 7.01 (s, 1 H, NH), 7.61 (d, J = 8.9 Hz, 2 H,
2 CHaryl), 8.22 (d, J = 8.9 Hz, 2 H, 2 CHaryl).
13C NMR (125.7 MHz, CDCl3): d = 14.03 (OCH2CH3), 14.38
(OCH2CH3), 29.82 [C(CH3)3], 53.10 [C(CH3)3], 60.06 (OCH2CH3),
62.17 (OCH2CH3), 89.87 (C3furan), 117.95 (C4furan), 123.79
(2 CHaryl), 124.37 (2 CHaryl), 134.99 (Cipso), 138.05 (Cipso-NO2),
145.90 (C5furan), 161.97 (C2furan), 164.28 (CO2Et), 165.05 (CO2Et).
(11) (a) Ugi, I. Angew. Chem., Int. Ed. Engl. 1982, 21, 810.
(b) Ugi, I.; Werner, B.; Dömling, A. Targets Heterocycl.
Syst. 2000, 4, 1. (c) Dömling, A. Curr. Opin. Chem. Biol.
2002, 6, 306. (d) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed.
2000, 39, 3168.
MS: m/z (%) = 406 (M+ + 2, 11), 405 (M+ + 1, 32), 404 (M+, 36),
374 (12), 348 (100), 302 (22), 274 (59), 150 (79), 104 (29), 76 (14),
57 (80), 41 (58).
Anal. Calcd for C20H24N2O7 (404.42): C, 59.40; H, 5.98; N, 6.93.
Found: C, 59.02; H, 6.01; N, 7.00.
(12) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. Engl. 1993, 32,
563.
(13) Shaabani, A.; Yavari, I.; Teimouri, M. B.; Bazgir, A.;
Bijanzadeh, H. R. Tetrahedron 2001, 57, 1375.
References
(1) (a) Johnson, A. W.; Tebby, J. C. J. Chem. Soc. 1961, 2126.
(b) Tebby, J. C.; Wilson, I. F.; Griffiths, D. V. J. Chem. Soc.,
Perkin Trans. 1. 1979, 2133.
Synthesis 2008, No. 11, 1788–1792 © Thieme Stuttgart · New York