"on water" organic synthesis: Three-component one-pot synthesis of novel bis(1-(cyclohexylamino)-1-oxoalkyl or aryl) fumarates

Article abstract of DOI:10.1007/s13738-013-0337-y

An efficient synthesis of novel bis(1-(cyclohexylamino)-1-oxoalkyl or aryl) fumarates (4a-k), considering as organic building blocks for natural products and drugs, via the reaction of fumaric acid, various aldehydes and cyclohexyl isocyanide in water usi

Full text of DOI:10.1007/s13738-013-0337-y

J IRAN CHEM SOC (2014) 11:659–664
DOI 10.1007/s13738-013-0337-y
ORIGINAL PAPER
‘‘On water’’ organic synthesis: three-component one-pot synthesis
of novel bis(1-(cyclohexylamino)-1-oxoalkyl or aryl) fumarates
•
M. Mamaghani F. Shirini N. O. Mahmoodi
•
•
•
A. Azimi-Roshan A. Monfared
Received: 1 March 2013 / Accepted: 25 August 2013 / Published online: 7 September 2013
Ó Iranian Chemical Society 2013
Abstract An efficient synthesis of novel bis(1-(cyclohex-
ylamino)-1-oxoalkyl or aryl) fumarates (4a–k), considering
as organic building blocks for natural products and drugs, via
thereactionoffumaricacid, variousaldehydesandcyclohexyl
isocyanide in water using one-pot three-component approach
under mild condition and without catalyst is described. This
rapid method produced the products in short reaction times
(10–15 min) and excellent yields (85–95 %) at room tem-
perature. The structures of the products were deduced from
their elemental analyses and spectroscopic data.
reaction temperature, use of high pressure and catalysts are
quite general. Another influence on reaction rate can be
observed in aqueous solvents. The use of water as a solvent
for organic transformations offers several ‘‘green chemis-
try’’ benefits [2]. Water is the lingua franca of life on our
planet and is the solvent of choice for nature to carry out her
syntheses [3]. Water possesses many unique physical and
chemical properties and considerable rate of acceleration is
often observed in reactions carried out under these condi-
tions over those in organic solvents [4]. For example, a
300-fold rate acceleration in the reaction of cyclopentadiene
with methyl vinyl ketone in water as compared to acetoni-
trile has been reported [5]. On the other hand, multicom-
ponent reactions (MCRs) are convergent reactions in which
three or more reagents are combined to react in a one-pot
procedure [6] and are very efficient synthetic methods [7].
Isocyanide-based multicomponent reactions (IMCRs) have
been of particular interest because of the large number of
starting materials available as well as powerful tools in the
modern drug discovery process and allow rapid, automated,
and high-throughput generation of organic compounds [8,
9]. The great potential of isocyanides for the development
of multicomponent reactions lies in the diversity of bond
forming processes available, their functional group toler-
ance, and the high levels of chemo-, regio-, and stereose-
lectivity are often observed [10]. They serve as
C-nucleophiles toward imines and aldehydes, resulting in
nitrilium ion electrophiles, which enable the Ugi 4CR and
Passerini 3CR, respectively [11]. This approach fills an
important niche in library synthesis by providing direct
access to library compounds and by serving as starting
points for diversity-oriented synthesis (DOS) [12]. MCRs
that involve isocyanides are by far the most versatile reac-
tions in terms of scaffolds and number of accessible com-
pounds [13]. Recent advances in the application of IMCRs
Keywords On water Á Green chemistry Á MCRs Á
Bis(1-(cyclohexylamino)-1-oxoalkyl or aryl)
fumarate Á Passerini reaction
Introduction
Acceleration of reactions is the most fundamental interest of
chemists [1] and several approaches such as increasing
The manuscript has been presented at the ‘‘1st National Conference
on Multi-Component Reaction’’ in Institute of Science and High
Technology and Environmental Sciences, Graduate University of
Advanced Technology, Kerman, Iran, 2012.
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-013-0337-y) contains supplementary
material, which is available to authorized users.
M. Mamaghani (&) Á F. Shirini Á N. O. Mahmoodi Á
A. Azimi-Roshan
Department of Chemistry, Faculty of Sciences,
University of Guilan, P.O. Box 41335-1914, Rasht, Iran
e-mail: m-chem41@guilan.ac.ir
A. Monfared
Department of Chemistry, University of Payamnoor of Tehran,
Tehran, Iran
123

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J IRAN CHEM SOC (2014) 11:659–664
Fig. 1 Hormone mimics
(erythropoietin)
Hormone Mimics (erythropoietin)
Synthesized by the ugi and Passerini reactions
O
R1
N
R1
N
O
O
O
R3
O
A
O
R3
R3
A
R3
N
H
N
H
N
N
H
H
R2
O
O
R2
R2
O
O
R2
Library 2
Passerini dicarboxylic acid
Library 1
Ugi dicarboxylic acid
in drug discovery summarize the various chemo types used
¨
to probe biological targets [14]. Domling et al. [15] pre-
Table 1 Synthesis of bis(1-(cyclohexylamino)-1-oxoalkyl or aryl)
fumarate derivatives (4a–k)
pared two libraries of several compounds each utilizing the
Ugi and Passerini reactions (Fig. 1) using rational design
approaches to mimic the hormone erythropoietin (EPO).
The compounds were screened as crude mixtures in a
functional EPO assay in search of agonists of the hormone.
Several promising compounds were identified and are now
in the process of further evaluation.
Product 4
R
MP (°C) Time (min) Yield (%)a,b
a
b
c
d
e
f
3-O2NC6H4
2-Thienyl
2-O2NC6H4
4-O2NC6H4
C6H5
245–247 10
210–212 12
214–216 10
180–182 10
220–222 12
250–252 10
230–232 15
90
95
90
95
85
90
90
95
85
95
90
4-ClC6H4
4-MeOC6H4
The Passerini reaction is an interesting reaction because
it is has 100 % atom-economy. This means that every atom
in the starting material is incorporated in the product.
Consequently, there is no intrinsic chemical waste associ-
ated with the reaction [16]. In this report, we attempt to use
Passerini reaction for the synthesis of novel bis(1-(cyclo-
hexylamino)-1-oxoalkyl or aryl) fumarates, performed on
water under the conditions defined by Sharpless and co-
workers: when insoluble reactant(s) are stirred in aqueous
emulsions or suspensions without the addition of any
organic co-solvents [17].
g
h
i
3,4-(MeO)2C6H3 214–217 10
Pyridin-4-yl
Pyridin-3-yl
n-C3H7
180–182 14
208–210 10
200–202 14
j
k
a
Isolated yields. b Identified by spectroscopic (FT-IR, 1H NMR, 13
NMR) and elemental analyses
C
and aromatic aldehydes (3) (2.0 mmol) and H2O (5 mL) in
a round bottom flask was stirred for 10–15 min at room
temperature. The solid product was isolated by filtration,
washed with 3 9 1 mL of 10 % NaHCO3 and 2 9 1 mL
water and dried under high vacuum. The product was re-
crystallized from ethanol to produce bis(1-(cyclohexyl-
amino)-1-oxoalkyl or aryl) fumarate derivatives (4a–k) as
pure crystalline products in 85–95 % yields (Table 1).
Experimental
Chemicals and apparatus
Melting points were measured on an Electrothermal 9100
apparatus. FT-IR spectra were determined on a Shimadzu
Selected spectral data of the products
1
FT-IR spectrometer. H NMR and 13C NMR spectra were
But-2-enedioic acid bis-[cyclohexylcarbamoyl-(3-nitro-
phenyl)-methyl] ester (4a)
recorded on a 500 MHz Bruker DRX-500 in CDCl3 as
solvent and TMS as an internal standard. Elemental anal-
yses were done on a Carlo-Erba EA1110 CNOS analyzer
and agreed with the calculated values. Chemicals were
purchased from Merck and Aldrich. All solvents used were
dried and distilled according to the standard procedures.
Light yellow powder; yield: 0.57 g (90 %); m.p.: 245–
247 °C; FT-IR (KBr): mmax = 3,270, 3,070, 2,930, 2,850,
1,720, 1,700, 1,655, 1,530, 1,350, 1,150 cm-1,1H NMR
(500 MHz, CDCl3): d = 0.98 (2H, m, CH), 1.10 (3H, m,
CH), 1.42 (1H, m, CH), 1.53 (3H, m, CH), 1.72 (1H, m,
CH), 3.51 (1H, m, CH), 6.03 (1H, s, NH), 6.94 (1H, s, CH),
7.39 (1H, t, J = 8 Hz, HAr), 7.44 (1H, d, J = 7.8 Hz,
HAr), 7.73 (1H, d, J = 7.5 Hz, HAr), 8.02 (1H, d,
J = 8.0 Hz, HAr), 8.25 (1H, s, CH). 13C NMR (125 MHz,
CDCl3): d = 24.8, 24.9, 25.6, 32.4, 32.6, 48.3 (CHNH),
General procedure for the synthesis of bis(1-
(cyclohexylamino)-1-oxoalkyl or aryl)
fumarate derivatives
A mixture of fumaric acid (1) (1.0 mmol, 0.106 g),
cyclohexyl isocyanide (2) (2.0 mmol, 0.218 g), aliphatic
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661
75.2 (CHO), 122.4, 124.0, 130.6, 133.9, 134.2, 138.0,
148.1, 163.7 (C=O, ester), 166.1 (C=O, amide) ppm. Anal.
Calcd. for C32H36N4O10: C, 60.37; H, 5.70; N, 8.80. Found:
C, 60.25; H, 5.74; N, 8.71.
J = 8.7 Hz, NH), 7.63 (2H, d, J = 8.7 Hz, HAr), 8.14
(2H, d, J = 8.7 Hz, HAr). 13C NMR (125 MHz, CDCl3):
d = 24.8, 24.9, 25.5, 32.4, 32.6, 48.3 (CHNH), 75.4
(CHO), 124.1, 128.8, 133.9, 143.0, 148.0, 163.7 (C=O,
ester), 165.9 (C=O, amide) ppm. Anal. Calcd. for
C32H36N4O10: C, 60.37; H, 5.70; N, 8.80. Found: C, 60.25;
H, 5.52; N, 8.85.
But-2-enedioic acid bis-(cyclohexylcarbamoyl-thiophen-2-
yl-methyl) ester (4b)
White powder; yield: 0.53 g (95 %); m.p.: 210–212 °C;
FT-IR (KBr): mmax = 3,280, 3,090, 2,940, 2,860, 1,730,
1,665, 1,560, 1,170, 970 cm-1,1H NMR (500 MHz,
CDCl3): d = 1.17 (3H, m, CH), 1.33 (2H, m, CH), 1.59
(1H, m, CH), 1.67 (2H, m, CH), 1.88 (2H, m, CH), 3.78
(1H, m, CH), 6.11(1H, s, NH), 6.36 (1H, s, CH), 6.97 (1H,
t, J = 4.29 Hz, HAr), 6.99 (1H, s, CH), 7.17 (1H, d,
J = 3.28 Hz, HAr), 7.33 (1H, d, J = 5.08 Hz, HAr). 13C
NMR (125 MHz, CDCl3): d = 23.5, 24.8, 25.4, 26.4, 29.4,
29.7, 31.3, 32.0, 32.2, 32.8, 48.7 (CHNH), 71.8 (CHO),
125.0, 127.0, 127.6, 128.6, 133.9, 135.2, 136.6, 163.0
(C=O, ester), 165.6 (C=O, amide) ppm. Anal. Calcd. for
C28H34N2O6S2: C, 60.19; H, 6.13; N, 5.01. Found: C,
60.11; H, 6.19; N, 4.95.
But-2-enedioic acid bis-(cyclohexylcarbamoyl-phenyl-
methyl) ester (4e)
White powder; yield: 0.46 g (85 %); m.p.: 220–222 °C;
FT-IR (KBr): mmax = 3,295, 3,070, 2,950, 2,860, 1,730,
1,660, 1,540, 1,150, 970 cm-1 1H NMR (500 MHz,
,
CDCl3): d = 1.18 (3H, m, CH), 1.21 (2H, m, CH), 1.38
(1H, m, CH), 1.72 (2H, m, CH), 1.93 (2H, m, CH), 3.82
(1H, m, CH), 5.93 (1H, t, J = 7.0 Hz, NH), 6.15 (1H, s,
CH), 7.06 (1H, d, J = 1.5 Hz, CH), 7.41 (3H, m,
HAr),7.46 (2H, m, HAr). 13C NMR (125 MHz, CDCl3):
d = 24.9, 25.0, 25.6, 32.5, 32.7, 48.2 (CHNH), 76.4
(CHO), 127.7, 127.8, 128.9, 129.1, 129.9, 133.9, 136.0,
163.9 (C=O, ester), 166.8 (C=O, amide) ppm. Anal. Calcd.
for C32H38N2O6: C, 70.31; H, 7.01; N, 5.12. Found: C,
70.14; H, 7.13; N, 5.02.
But-2-enedioic acid bis-[cyclohexylcarbamoyl-(2-nitro-
phenyl)-methyl] ester (4c)
But-2-enedioic acid bis-[(4-chloro-phenyl)-
cyclohexylcarbamoyl-methyl] ester (4f)
Light yellow powder; yield: 0.57 g (90 %); m.p.: 214–
216 °C; FT-IR (KBr): mmax = 3,320, 3,050, 2,960, 2,860,
1
1,720, 1,670, 1,570, 1,530, 1,340, 1,150, 1,020 cm-1, H
White powder; yield: 0.55 g (90 %); m.p.: 250–252 °C;
FT-IR (KBr): mmax = 3,290, 3,060, 2,940, 2,860, 1,730,
1,660, 1,550, 1,250, 1,090, 1,020 cm-1,1H NMR
(500 MHz, CDCl3): d = 1.06 (3H, m, CH), 1.22 (2H, m,
CH), 1.52 (1H, m, CH), 1.60 (2H, m, CH), 1.71 (1H, m,
CH), 1.79 (1H, m, CH), 3.64 (1H, m, CH), 5.98 (1H, s,
CH), 6.65 (1H, d, J = 7.9 Hz, NH), 6.94 (1H, d,
J = 1.86 Hz, CH), 7.24 (2H, d, J = 8.5 Hz, HAr), 7.33
(2H, d, J = 8.5 Hz, HAr). 13C NMR (125 MHz, CDCl3):
d = 24.8, 25.4, 32.8, 32.9, 48.5, 48.6 (CHNH), 73.4
(CHO), 75.7 (CHO), 128.2, 128.99, 129.0, 129.2, 133.5,
133.9, 135.4, 166.1 (C=O, ester), 170.6 (C=O, amide) ppm.
Anal. Calcd. for C32H36Cl2N2O6: C, 62.44; H, 5.89; N,
4.55. Found: C, 62.27; H, 5.78; N, 4.41.
NMR (500 MHz, CDCl3): d = 1.17 (2H, m, CH),
1.24–1.37 (3H, m, CH), 1.57 (2H, m, CH), 1.69 (1H, m,
CH), 1.78 (1H, m, CH), 1.95 (1H, m, CH), 3.75 (1H, m,
CH), 6.28 (1H, d, J = 8.0 Hz, NH), 6.68 (1H, d,
J = 3.0 Hz, CH), 7.03 (1H, s, CH), 7.55 (1H, t,
J = 7.8 Hz, HAr), 7.69 (1H, t, J = 7.5 Hz, HAr), 7.82
(1H, dd, J = 7.0, 4.0 Hz, HAr), 8.02 (1H, d, J = 8.18 Hz,
HAr). 13C NMR (125 MHz, CDCl3): d = 24.6, 25.4, 32.6,
32.7, 32.8, 48.7 (CHNH), 71.6 (CHO), 124.9, 129.8,
129.9, 130.2, 133.8, 134.0, 148.0, 163.2 (C=O, ester),
165.1 (C=O, amide) ppm. Anal. Calcd. for C32H36N4O10:
C, 60.37; H, 5.70; N, 8.80. Found: C, 60.29; H, 5.55; N,
8.68.
But-2-enedioic acid bis-[(4-nitro-phenyl)-
cyclohexylcarbamoyl-methyl] ester (4d)
But-2-enedioic acid bis-[cyclohexylcarbamoyl-(4-methoxy-
phenyl)-methyl] ester (4g)
Light yellow powder; yield: 0.61 g (95 %); m.p.:
180–182 °C; FT-IR (KBr): mmax = 3,280, 3,050, 2,950,
2,840, 1,710, 1,655, 1,610, 1,540, 1,340, 1,260, 1,200,
1,160 cm-1,1H NMR (500 MHz, CDCl3): d = 1.04–1.26
(5H, m, CH), 1.52 (1H, m, CH), 1.62 (2H, m, CH), 1.71
(1H, m, CH), 1.80 (1H, m, CH), 3.63 (1H, m, CH), 6.12
(1H, s, CH), 7.02 (1H, d, J = 1.9 Hz, CH), 7.04 (1H, t,
White powder; yield: 0.55 g (90 %); m.p.: 230–232 °C;
FT-IR (KBr): mmax = 3,300, 3,050, 2,910, 2,860, 1,730,
1,660, 1,545, 1,510, 1,250, 1,150, 1,030 cm-1,1H NMR
(500 MHz, CDCl3): d = 1.19 (3H, m, CH), 1.38 (2H, m,
CH), 1.65 (1H, m, CH), 1.73 (2H, m, CH), 1.92 (2H, m,
CH), 3.81 (1H, s, CH), 3.83 (3H, m, OCH3), 5.84 (1H, t,
J = 7.15 Hz, NH), 6.11 (1H, s, CH), 6.93 (2H, d,
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But-2-enedioic acid bis-(cyclohexylcarbamoyl-pyridin-3-
yl-methyl) ester (4j)
J = 8.7 Hz, HAr), 7.02 (1H, d, J = 1 Hz, CH), 7.38 (2H,
d, J = 8.7 Hz, HAr). 13C NMR (125 MHz, CDCl3):
d = 24.8, 24.81, 25.4, 32.9, 33.0, 48.4 (CHNH), 55.4
(CH3O), 76.1 (CHO), 114.3, 127.1, 129.3, 133.9, 160.3
(C=O, ester), 163.2, 166.8 (C=O, amide) ppm. Anal. Calcd.
for C34H42N2O8: C, 67.31; H, 6.98; N, 4.62. Found: C,
67.19; H, 6.87; N, 4.51.
Light brown powder; yield: 0.52 g (95 %); m.p.: 208–
210 °C; FT-IR (KBr): mmax = 3,295, 3,070, 2,960, 1,730,
1,660, 1,540, 1,320, 1,270, 1,160 cm-1,1H NMR (500 MHz,
CDCl3): d = 1.11 (3H, m, CH), 1.26 (2H, m, CH), 1.52 (1H,
m, CH), 1.63 (2H, m, CH), 1.75 (1H, m, CH), 1.82 (1H, m,
CH), 3.67 (1H, m, CH), 6.07 (1H, d, J = 1.77 Hz, CH), 6.81
(1H, d, J = 6.87 Hz, NH), 6.98 (1H, s, CH), 7.24 (1H, m,
HAr), 7.76 (1H, dt, J = 8.0, 1.82 Hz, HAr), 8.52 (1H, dd,
But-2-enedioic acid bis-[cyclohexylcarbamoyl-(3,4-
dimethoxy-phenyl)-methyl] ester (4h)
J = 4.8, 1.46 Hz, HAr), 8.64 (1H, d, J = 2.0 Hz, HAr). 13
C
White powder; yield: 0.63 g (95 %); m.p.: 214–217 °C;
FT-IR (KBr): mmax = 3,280, 3,050, 2,920, 2,860, 1,730,
NMR (125 MHz, CDCl3): d = 25.2, 25.3, 25.9, 32.0, 32.9,
48.7 (CHNH), 74.7 (CHO), 124.5, 132.3, 134.3, 135.7,
149.4, 150.7, 164.2 (C=O, ester), 166.7 (C=O, amide) ppm.
Anal. Calcd. for C30H36N4O6: C, 65.68; H, 6.61; N, 10.21.
Found: C, 65.52; H, 6.49; N, 10.14.
1,660, 1,600, 1,560, 1,150 cm-1 1H NMR (500 MHz,
,
CDCl3): d = 1.15 (3H, m, CH), 1.36 (2H, m, CH), 1.60
(1H, m, CH), 1.68 (2H, m, CH), 1.88 (2H, m, CH),
3.79 (1H, m, CH), 3.87 (3H, s, OCH3), 3.88 (3H, s,
OCH3), 5.78 (1H, d, J = 8.19 Hz, NH), 6.06 (1H, s,
CH), 6.85 (1H, d, J = 8.21 Hz, HAr), 6.95 (1H, d,
J = 1.91 Hz, HAr), 6.98 (1H, dd, J = 8.21, 1.91 Hz,
HAr), 7.02 (1H, d, J = 1.18 Hz, CH). 13C NMR
(125 MHz, CDCl3): d = 24.8, 25.4, 32.9, 33.0, 48.5
(CHNH), 55.96 (CH3O), 55.99 (CH3O), 76.3 (CHO),
110.7, 111.1, 120.6, 127.3, 133.9, 149.2, 149.9, 163.3
(C=O, ester), 166.7 (C=O, amide) ppm. Anal. Calcd. for
C36H46N2O10: C, 64.85; H, 6.95; N, 4.20. Found: C,
64.73; H, 6.82; N, 4.10.
But-2-enedioic acid bis-(1-cyclohexylcarbamoyl-butyl)
ester (4k)
White powder; yield: 0.43 g (90 %); m.p.: 200–202 °C;
FT-IR (KBr): mmax = 3,285, 3,080, 2,910, 2,860, 1,730,
1,655, 1,550, 1,380, 1,310, 1,240, 1,145, 970 cm-1,1H
NMR (500 MHz, CDCl3): d = 0.97 (3H, m, CH3), 1.20
(3H, m, CH), 1.42 (4H, m, CH), 1.66 (1H, m, CH), 1.73
(2H, m, CH), 1.91 (4H, m, CH), 3.82 (1H, m, CH), 5.24
(1H, t, J = 5.76 Hz, CH), 5.80 (1H, d, J = 7.68 Hz, NH),
7.02 (1H, d, J = 1.0 Hz, CH). 13C NMR (125 MHz,
CDCl3): d = 14.1, 18.5, 25.2, 25.8, 33.4, 34.0, 34.3, 48.6
(CHNH), 75.5 (CHO), 134.3, 164.0 (C=O, ester), 168.4
(C=O, amide) ppm. Anal. Calcd. for C26H42N2O6: C,
65.25; H, 8.84; N, 5.85. Found: C, 65.11; H, 8.65; N, 5.60.
But-2-enedioic acid bis-(cyclohexylcarbamoyl-pyridin-4-
yl-methyl) ester (4i)
Light brown powder; yield: 0.47 g (85 %); m.p.: 180–
182 °C; FT-IR (KBr): mmax = 3,366, 3,074, 2,932, 2,855,
1,710, 1,655, 1,520, 1,263, 1,022 cm-1
,
1H NMR
(500 MHz, CDCl3): d = 1.17 (2H, m, CH), 1.35 (2H, m,
CH), 1.63 (2H, m, CH), 1.70 (2H, m, CH), 1.90 (2H, m,
CH), 3.78 (1H, m, CH), 5.91 (1H, d, J = 8.08 Hz, NH),
6.09 (1H, s, CH), 7.11 (1H, s, CH), 7.38 (2H, d,
J = 5.92 Hz, HAr), 8.65 (2H, d, J = 5.92 Hz, HAr) ppm.
Anal. Calcd. for C30H36N4O6: C, 65.68; H, 6.61; N, 10.21.
Found: C, 65.50; H, 6.68; N, 10.05.
Results and discussion
Chemical transformations in aqueous solvents have
attracted the attention of scientists for many years and have
been regularly and comprehensively reviewed in the liter-
ature [4, 18–24].
Scheme 1 Synthesis of bis(1-(cyclohexylamino)-1-oxoalkyl or aryl) fumarates (4a–k)
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J IRAN CHEM SOC (2014) 11:659–664
663
1
23.5–32.8 ppm. It is worth mentioning that H NMR and
FT-IR spectra as well as elemental analysis all confirmed
the structure of the bis(1-(cyclohexylamino)-1-oxoalkyl or
aryl) fumarates (4a–k).
Table 2 Effect of various solvents in the synthesis of 4a under mild
condition
Solvent
Time (min)
Yield (%)a
DMF
120
100
140
120
10
30
35
30
30
90
The effect of several solvents (1,4-dioxane, CH3CN,
DMF, CH2Cl2, H2O) on the efficiency of the reaction was
also examined by using synthesis of 4a as model reaction.
The results are presented in Table 2. This study revealed
that H2O is the solvent of choice.
CH3CN
CH2Cl2
1,4-Dioxane
H2O
a
Mechanistically the formation of the products (4a–k)
can be visualized by initial nucleophilic attack of isocyano-
cyclohexane (2) on aldehyde to form intermediate 5, fol-
lowed by nucleophilic addition of the carboxylate ion to
intermediate 5 and subsequent rearrangement to furnish the
desired Passerini compounds (Scheme 2). In addition due
to mild reaction conditions used in this protocol the trans-
stereochemistry of the starting fumaric acid is retained in
the final product.
Isolated yields
Following our preliminary experiments demonstrating
that Passerini reaction is significantly accelerated on water,
and in connection with our continued research on envi-
ronmentally benign methodologies in organic synthesis
[25–31], we became interested in developing versatile and
efficient one-pot synthesis of bis(1-(cyclohexylamino)-1-
oxoalkyl or aryl) fumarates (4a–k) utilizing the reaction of
fumaric acid (1) (1 mmol), cyclohexyl isocyanide (2)
(2 mmol) and aldehydes (3a–k) (2 mmol) in water at room
temperature (Scheme 1). This rapid method produced the
products in short reaction times (10–15 min) and excellent
yields (85–95 %) (Table 1). The structures of the products
were deduced from their elemental analyses and spectro-
scopic data.
In this study, for cyclohexyl ring carbons in the 13C
NMR spectra due to symmetrical nature of the products,
six distinct peaks were observed at region 24.6–48.7 ppm.
However, in the case of 4b, because of the symmetry
distortion of the molecule, in the 13C NMR spectrum two
sets of peaks (one at 48.3 ppm for the ipso-carbon of
cyclohexyl ring and 10 peaks for the remaining carbons
of cyclohexyl rings) appeared at the expected region
Conclusions
In conclusion, we have developed an efficient synthesis of
novel bis(1-(cyclohexylamino)-1-oxoalkyl or aryl) fuma-
rate derivatives (4a–k) via the reaction of fumaric acid,
various aldehydes and cyclohexyl isocyanide in water
without catalyst using one-pot three-component approach
which could be used as organic building blocks for natural
products and drugs. The reaction conditions are mild and
the reaction gives excellent yields of the products. This
method does not involve the use of toxic solvents, catalyst
and tedious workup procedure and thus is an environ-
mentally friendly process.
Scheme 2 Proposed
mechanism for the formation of
bis(1-(cyclohexylamino)-1-
oxoalkyl or aryl) fumarate
derivatives
123

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J IRAN CHEM SOC (2014) 11:659–664
Acknowledgments We thank the Research Council of University of
Guilan for partial support of this study.
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