Synthesis of bis(aminofuryl)bicinchoninic amides by a one-pot three-component reaction of isocyanides, acetylenic esters, and bicinchoninic acid

Article abstract of DOI:10.1055/s-2008-1067246

A simple synthesis of dialkyl 2-(alkylamino)-5-[alkyl({2-[4-({alkyl[5- (alkylamino)-3,4-bis(alkoxycarbonyl)-2-furyl]amino}carbonyl)-2-quinolyl] -4-quinolyl}carbonyl)amino]-3,4-furandicarboxylate derivatives is described. This involves reaction of isocyanides, dialkyl acetylenedicarboxylates, and bicinchoninic acid (BCA) in MeCN-THF at 25°C for 36 hours. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067246

PAPER
2929
Synthesis of Bis(aminofuryl)bicinchoninic Amides by a One-Pot
Three-Component Reaction of Isocyanides, Acetylenic Esters, and
Bicinchoninic Acid
S
ynthesis of Bis(am
b
inofuryl)bic
d
inchoninic
Ao
mides lali Alizadeh,*a Qasem Oskueyan,a Sadegh Rostamnia,a Abbass Ghanbari-Niaki,b Ali Rreza Mohebbic
a
b
c
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran 18716, Iran
Department of Physical Education & Sports Science, Tarbiat Modares University, P.O. Box 14115-175, Tehran 18716, Iran
Otto-Diels-Institut für Organische Chemie, Christian-Albrechts University of Kiel, 24098 Kiel, Germany
Fax +98(21)88006544; E-mail: abdol_alizad@yahoo.com; E-mail: aalizadeh@modares.ac.ir
Received 9 May 2008; revised 21 May 2008
Although we have not established the mechanism of this
reaction, a possible explanation is proposed in Scheme 2.
On the basis of the well-established chemistry of isocya-
nides,2,3,5,10–15 it is reasonable to assume that the function-
Abstract: A simple synthesis of dialkyl 2-(alkylamino)-5-
[alkyl({2-[4-({alkyl[5-(alkylamino)-3,4-bis(alkoxycarbonyl)-2-fu-
ryl]amino}carbonyl)-2-quinolyl]-4-quinolyl}carbonyl)amino]-3,4-
furandicarboxylate derivatives is described. This involves reaction
of isocyanides, dialkyl acetylenedicarboxylates, and bicinchoninic alized diaminofuran 4 apparently results from the initial
acid (BCA) in MeCN–THF at 25 °C for 36 hours.
addition of the isocyanide to the acetylenic system and
subsequent protonation of the 1:1 adduct 5 by compound
3, followed by the attack of the carboxylate anion on the
positively charged ion of 6 to form imidoyl carboxylate 7
as an intermediate. This intermediate rearranges10–13 un-
der the reaction conditions employed to produce the inter-
mediate 8, followed by its trapping with an isocyanide, to
give the intermediate 9, which leads to compound 4
(Scheme 2) by a 1,5-H-shift.11,13
Key words: dialkyl acetylenedicarboxylate, isocyanide, bicincho-
ninic acid, multicomponent reaction, bicinchoninic amide
A general way to improve synthetic efficiency and also to
address other criteria is the development of new types of
multicomponent reactions.1 Multicomponent reactions
(MCRs), by virtue of their convergence, productivity, fac-
ile execution, and generally high yields of products, have
attracted much attention from the point of combinatorial
chemistry.1–6 Of pivotal importance in multicomponent
area are the isocyanide-based MCRs such as the versatile
Ugi and Passerini reactions.2,3,5
In view of the success of the above reaction, we have ex-
plored the use of the biochemically interesting bicincho-
ninic acid (BCA) as the third component in this reaction.
Herein, we report the results of an extended investigation
of the reactivity of the intermediate zwitterions with a bi-
functional heteroaromatic acid in MeCN–THF. The prod-
ucts are bis(aminofuryl)bicinchoninic amide derivatives.
Passerini’s three-component reactions of isocyanides, al-
dehydes, and carboxylic acids produce a-amido esters that
can be used in the synthesis of a variety of drugs such as
euristatin6 and hydrastine.7 Also the production of many
drugs such as benzodiazepine8 and carbacefem9 using Ugi
reaction was reported.
We prepared the bicinchoninic acid by the reaction of the
sodium salt of bicinchoninic acid with hydrochloric acid.
The reaction of alkyl isocyanides and dialkyl acetylenedi-
carboxylates in the presence of bicinchoninic acid pro-
ceeded spontaneously at 25 °C in MeCN–THF and was
completed within 36 hours, to produce dialkyl 2-(alkyl-
amino)-5-[alkyl({2-[4-({alkyl[5-(alkylamino)-3,4-bis(al-
koxycarbonyl)-2-furyl]amino}carbonyl)-2-quinolyl]-4-
quinolyl}carbonyl)amino]-3,4-furandicarboxylate deriv-
atives in 37–52% yields (Table 1).
We recently reported a new class of isocyanide based
multicomponent reaction (IMCRs/DMAD) mediated by
zwitterionic intermediates and Dimroth-type rearrange-
ment.10–14 Treatment of nicotinic or isonicotinic acid with
dialkyl acetylenedicarboxylate and alkyl isocyanide at
25 °C led to the formation of the nicotinamide and
isonicotinamide derivatives (Scheme 1).13
ROC
N
COR
NH
COR
O
CO2H
THF
r.t.
2
+
+
N
C
O
N
COR
N
1
2
3
4
Scheme 1
SYNTHESIS 2008, No. 18, pp 2929–2932
x
x.
x
x
.
2
0
0
8
Advanced online publication: 22.08.2008
DOI: 10.1055/s-2008-1067246; Art ID: Z10508SS
© Georg Thieme Verlag Stuttgart · New York

2930
A. Alizadeh et al.
PAPER
COR
3
1 +
2
N
C
C
C COR
5
O
N
CO2
CHCOR
COR
COR
O
N
C
C
C
COR
H
N
N
7
6
N
N
C
O
O
O
O
H
CHCOR
4
N
COR
COR
N
COR
N
N
9
8
Scheme 2
Table 1 Compounds 12 Prepared
1
4
R
N
C
CO2R2
R1
10
R2O2C
+
N
MeCN–THF
r.t., 36 h
O
2R2O2C
CO2R2
R1
N
HN
R1
O
11
O
NH
N
R1
+
O
N
O
OH
CO2R2
R2O2C
12
N
N
HO
O
Compound
12a
R1
R2
Me
Et
Yield (%)
t-Bu
t-Bu
43
52
40
37
12b
12c
c-C6H11
c-C6H11
Me
Et
12d
The structures of compounds 12a–d were deduced from alkyl groups, which exhibit characteristic signals with ap-
1
their elemental analyses, IR, and high-field H and 13C propriate chemical shifts.
NMR spectra. The mass spectrum of 12a displayed the
molecular ion peak at m/z = 961, which is consistent with
the 2:4:1 adduct of dimethyl acetylenedicarboxylate, tert-
butyl isocyanide, and bicinchoninic acid. The IR spectrum
In summary, the reaction between isocyanides and dialkyl
acetylenedicarboxylates in the presence of bicinchoninic
acid provides a simple one-pot three-component reaction
entry into the synthesis of bis(aminofuran)bicinchoninic
of 12a exhibited absorption band due to the carbonyl
groups of ester and amide at 1722, 1710, and 1665 cm–1,
respectively, and NH groups at 3325 cm–1. The 1H NMR
spectrum of 12a exhibited six single sharp lines readily
recognized as arising from tert-butyl groups (1.65 and
1.66) and methoxy groups (3.47 and 3.48) along with two
NH groups (6.51 and 6.59). The quinoline moiety gave
rise to characteristic signals in the aromatic region of the
amide derivatives,15 which may be of interest in the phar-
maceutical chemistry. The present method carries the ad-
vantage of being performed under neutral conditions and
requires no activation or modification of the adducts.
The sodium salt of bicinchoninic acid, dimethyl and diethyl acety-
lenedicarboxylates, tert-butyl and cyclohexyl isocyanides were ob-
tained from Merck (Germany) and Fluka (Switzerland), and were
used without further purification. Melting points were measured on
an Electrothermal 9100 apparatus. Mass spectra were recorded on a
1
spectrum.The H and 13C NMR spectra of compounds
12b–d are similar to those of 12a, except for the ester and
Synthesis 2008, No. 18, 2929–2932 © Thieme Stuttgart · New York

PAPER
Synthesis of Bis(aminofuryl)bicinchoninic Amides
2931
Maldi mass spectrometer; MALDI-TOF spectra were measured on
a Bruker Biflex III with a 19 kV acceleration voltage. trans-2-[3-(4-
159.10, 159.23 (2 × C2, Ar), 162.53, 162.57, 164.26, 164.38 (4 ×
CO2Et), 169.62, 169.72 (2 × CON).
HRMS: m/z [M]+ calcd for C56H68N6O12: 1017.18; found: 1017.39.
tert-Butylphenyl)-2-methyl-2-propenylidene]malononitrile
was
used as the matrix, as a saturated solution in CH2Cl2. Ionization was
effected with a nitrogen laser at 337 nm, detecting of molecules by
molecular weight about 1000. Elemental analyses were performed
using a Heraeus CHN–O–Rapid analyzer. 1H and 13C NMR spectra
were measured (CDCl3 solution) with a Bruker DRX-500 Avance
spectrometer at 500.13 and 125.8 MHz, respectively. IR spectra
were recorded on a Shimadzu IR-460 spectrometer. Chromatogra-
phy columns were prepared from Merck silica gel (230–240 mesh).
Anal. Calcd for C56H68N6O12 (1017): C, 66.13; H, 6.74; N, 8.26.
Found: C, 66.15; H, 6.72; N, 8.34.
Dimethyl 2-(Cyclohexylamino)-5-[cyclohexyl({2-[4-({cyclohex-
yl[5-(cyclohexylamino)-3,4-bis(methyloxycarbonyl)-2-fur-
yl]amino}carbonyl)-2-quinolyl]-4-quinolyl}carbonyl)amino]-
3,4-furandicarboxylate (12c)
Yield: 0.42 g (40%); yellow powder; mp 142–144 °C.
Dimethyl 2-(tert-Butylamino)-5-[tert-butyl({2-[4-({tert-butyl[5-
(tert-butylamino)-3,4-bis(methyloxycarbonyl)-2-furyl]ami-
no}carbonyl)-2-quinolyl]quinolyl}carbonyl)amino]-3,4-furan-
dicarboxylate (12a); Typical Procedure
To a magnetically stirred solution of dimethyl acetylenedicarboxy-
late (0.28 g, 2 mmol) and bicinchoninic acid (0.34 g, 1 mmol) in
MeCN–THF (5 mL) was added dropwise a solution of tert-butyl
isocyanide (0.33 g, 4 mmol) in anhyd MeCN–THF (3 mL) at 25 °C
over 15 min. Then the mixture was allowed to stir for 36 h. The sol-
vent was removed under reduced pressure, and the residue was sep-
arated by silica gel (Merck 230–240 mesh) column chromatography
using hexane–EtOAc mixture as eluent; yield: 0.41 g (42%); yellow
powder; mp 117–119 °C.
IR (KBr): 3330 (NH), 1726, 1707 (CO2Me), 1666 (CON), 1606,
1537 (Ar), 1246, 1210 cm–1 (C–O).
1H NMR (CDCl3, 500 MHz): d = 1.21–2.20 (40 H, m, 20 × CH2 cy-
clohexyl), 3.31 (2 H, m, 2 × CHN), 3.51, 3.77 (12 H, s, 4 × OCH3),
4.46 (2 H, m, 2 × CHN), 6.37, 6.39 (2 H, s, 2 × NH), 7.54 (2 Harom
,
t, J = 7.0 Hz), 7.67 (2 Harom, t, J = 6.9 Hz), 7.97 (2 Harom, d, J = 7.9
Hz), 8.10 (2 Harom, d, J = 8.4 Hz), 8.64 (2 Harom, s).
13C NMR (CDCl3, 125 MHz): d = 22.77–26.92, 31.86–32.66 (20 ×
CH2 cyclohexyl), 49.07 (2 × CHN), 50.80 (2 × OCH3), 51.22
(CHN), 51.73 (CHN), 57.14 (2 × OCH3), 85.02 (2 × C3 furan),
115.49, 116.35 (2 × C4 furan), 124.61 (2 × Cipso-CON), 125.52 (2 ×
CH, Ar), 127.11 (2 × C4a), 128.20 129.01 129.41, 130.36 (8 × CH,
Ar), 135.96 (2 × C8a), 142.80, 147.89 (2 × C5 furan), 154.60 (2 ×
C2 furan), 159.15 (2 × C2, Ar), 162.45, 164.46 (4 × CO2Me),
169.12 (2 × CON).
IR (KBr): 3325 (NH), 1722, 1710 (CO2Me), 1665 (CON), 1596,
1539 (Ar), 1246, 1213 cm–1 (C–O).
1H NMR (CDCl3, 500 MHz): d = 1.65, 1.66 (36 H, s, 4 × t-C4H9),
3.47, 3.48 (12 H, s, 4 × OCH3), 6.51, 6.59 (2 H, s, 2 × NH), 7.54 (2
HRMS: m/z [M]+ calcd for C60H68N6O12: 1065.22; found: 1065.37.
Anal. Calcd for C60H68N6O12 (1065): C, 67.65; H, 6.43; N, 7.89.
Found: C, 67.71; H, 6.45; N, 8.01.
Harom, t, J = 8.1 Hz), 7.66 (2 Harom, t, J = 7.1 Hz), 7.92 (2 Harom, d,
J = 8.0 Hz), 8.08 (2 Harom, dd, J = 8.2, 4.0 Hz), 8.61 (2 Harom, s).
13C NMR (CDCl3, 125 MHz): d = 28.01 [2 × C(CH3)3], 29.57, 29.74
(2 × C(CH3)3], 50.75, 50.80, 51.69, 51.74 (4 × CMe3), 52.42, 62.08,
62.10 (4 × OCH3), 86.05 (2 × C3 furan), 115.06, 115.34 (2 × C4 fu-
ran), 124.43, 124.46 (2 × Cipso-CON), 125.26 (2 × CH, Ar), 127.17,
127.22 (C-4a), 128.18, 128.99, 129.38, 129.40, 130.17, 130.20 (8
CH, Ar), 137.81, 137.95 (2 × C8a), 143.71, 147.73 (2 × C5 furan),
154.39, 154.46 (2 × C2 furan), 159.15, 159.25 (2 × C2, Ar), 162.56,
162.65, 164.47, 164.62 (4 × CO2Me), 169.62, 169.71 (2 × CON).
Diethyl 2-(Cyclohexylamino)-5-[cyclohexyl({2-[4-({cyclohex-
yl[5-(cyclohexylamino)-3,4-bis(ethyloxycarbonyl)-2-furyl]ami-
no}carbonyl)-2-quinolyl]-4-quinolyl}carbonyl)amino]-3,4-
furandicarboxylate (12d)
Yield: 0.41 g (37%); yellow powder; mp 217–219 °C.
IR (KBr): 3270 (NH), 1722 (CO2Et), 1665 (CON), 1594, 1523 (Ar),
1248, 1176 cm–1 (C–O).
1H NMR (CDCl3, 500 MHz): d = 1.05–1.08 (12 H, m, 4
× OCH2CH3), 1.23–2.20 (40 H, m, 20 × CH2 cyclohexyl), 3.27 (2 H,
m, 2 × CHN), 3.95–4.25 (8 H, m, 4 × OCH2CH3), 4.66 (2 H, m, 2 ×
CHN), 6.37 (1 H, s, NH), 6.39 (1 H, s, NH), 7.53 (2 Harom, t, J = 7.2
Hz), 7.67 (2 Harom, t, J = 7.6 Hz), 7.99 (2 Harom, d, J = 8.1 Hz), 8.10
(2 Harom, d, J = 8.3 Hz), 8.73 (2 Harom, s).
HRMS: m/z [M]+ calcd for C52H60N6O12: 961.07; found: 961.35.
Anal. Calcd for C52H60N6O12 (961): C, 64.99; H, 6.29; N, 8.74.
Found: C, 65.10; H, 6.30; N, 8.71.
Diethyl 2-(tert-Butylamino)-5-[tert-butyl({2-[4-({tert-butyl[5-
(tert-butylamino)-3,4-bis(ethyloxycarbonyl)-2-furyl]ami-
no}carbonyl)-2-quinolyl]-4-quinolyl}carbonyl)amino]-3,4-
furandicarboxylate (12b)
13C NMR (CDCl3, 125 MHz): d = 13.69, 14.16 (4 × CH3CH2O),
21.41–25.78, 32.44–33.29 (20 × CH2 cyclohexyl), 51.12 (2 ×
CH3CH2O), 57.28 (2 × CHN), 59.47 (2 × CHN), 61.12 (2
× OCH2CH3), 85.36 (2 × C3 furan), 115.86, 116.44 (C4 furan),
124.62 (2 × Cipso-CON), 125.30 125.56 (2 × CH, Ar), 127.08 (2 ×
C4a), 128.22, 129.03, 129.39, 130.23 (8 × CH, Ar), 137.86 (2 ×
C8a), 142.94, 147.91 (C5 furan), 154.66 (2 × C2 furan), 159.20 (C2,
Ar), 162.29, 164.23 (4 × CO2Et), 169.21 (2 × CON).
Yield: 0.58 g (52%); yellow powder; mp 256–258 °C.
IR (KBr): 3335 (NH), 1716, 1743 (CO2Et), 1669 (CON), 1593,
1540 (Ar), 1248, 1210 cm–1 (C–O).
1H NMR (CDCl3, 500 MHz): d = 0.82–0.86, 1.02–1.05 (12 H, m, 4
× OCH2CH3), 1.09, 1.14 1.65, 1.66 (36 H, s, 4 × t-C4H9), 3.86–3.92,
3.96–4.00, 4.08–4.10 (8 H, m, 4 × OCH2CH3), 6.54, 6.59 (2 H, s, 2
× NH), 7.54 (2 Harom, t, J = 8.0 Hz), 7.67 (2 Harom, t, J = 7.1 Hz), 7.98
(2 Harom, dd, J = 8.1, 5.0 Hz), 8.12 (2 Harom, d, J = 8.3, 1.1 Hz), 8.69
(2 Harom, s).
HRMS: m/z [M]+ calcd for C64H76N6O12: 1121.33; found: 1121.39.
Anal. Calcd for C64H76N6O12 (1121): C, 68.55; H, 6.83; N, 7.49.
Found: C, 68.60; H, 6.75; N, 7.43.
13C NMR (CDCl3, 125 MHz): d = 13.49, 14.11 (4 × OCH2CH3),
28.02 [2 × C(CH3)3], 29.66, 29.76 [2 × C(CH3)3], 52.37 (2 ×
OCH2CH3), 59.42, 59.46, 61.01, 61.11 (4 × CMe3), 62.10, 62.16 (2
× OCH2CH3), 86.28 (2 × C3 furan), 115.40, 115.46 (2 × C4 furan),
124.50 (2 × Cipso-CON), 125.25, 125.31 (2 × CH, Ar), 127.15 (2 ×
C4a), 127.26, 129.43, 130.10 (8 × CH, Ar), 137.72, 137.74 (2 ×
C8a), 143.90, 147.76 (2 × C5 furan), 154.47, 154.50 (2 × C2 furan),
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Synthesis 2008, No. 18, 2929–2932 © Thieme Stuttgart · New York