A novel one-pot synthesis of symmetric dialkyl 2,5-bis((2,6-dimethylphenyl) imino)-2,5-dihydrofuran-3,4-dicarboxylate derivatives

Article abstract of DOI:10.1007/s11164-012-1002-2

An efficient one-pot, three-component synthesis of symmetric dialkyl 2,5-bis((2,6-dimethylphenyl)imino)-2,5-dihydrofuran-3,4-dicarboxylate derivatives is described. The advantages of the method are high bond-forming efficiency, simple operation, and high yield. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s11164-012-1002-2

Res Chem Intermed
DOI 10.1007/s11164-012-1002-2
A novel one-pot synthesis of symmetric dialkyl 2,
5-bis((2,6-dimethylphenyl)imino)-2,5-dihydrofuran-3,
4-dicarboxylate derivatives
•
Malek Taher Maghsoodlou
Khatereh Khandan-Barani Nourallah Hazeri
•
•
•
Sayyed Mostafa Habibi-Khorasani Anthony C. Willis
Received: 10 November 2012 / Accepted: 25 December 2012
Ó Springer Science+Business Media Dordrecht 2013
Abstract An efficient one-pot, three-component synthesis of symmetric dialkyl 2,5-
bis((2,6-dimethylphenyl)imino)-2,5-dihydrofuran-3,4-dicarboxylate derivatives is descri-
bed. The advantages of the method are high bond-forming efficiency, simple operation, and
high yield.
Keywords Isocyanide Á Isocyanate Á Three-component reaction Á Bisiminofuran Á
Acetylenic esters
Introduction
Since the beginning of the 1980s the chemistry of isocyanides has been important in
the development of high-throughput screening and the creation of molecular
diversity by use of multicomponent reactions (MCRs) [1]. Although several classes
of compound participate in MCRs, the most successful MCRs are isocyanide-based,
for example the Passerini three-component reaction (P-3CR) and the Ugi four-
component reaction (U-4CR) [2, 3]. MCRs are fundamental to both combinatorial
chemistry and diversity-oriented synthesis and have, thus, been of central
importance in the development of modern synthetic methodology for pharmaceu-
tical and drug discovery research [4–6].
M. T. Maghsoodlou (&) Á N. Hazeri Á S. M. Habibi-Khorasani
Department of Chemistry, Faculty of Science, The University of Sistan and Baluchestan,
P.O. Box 98135-674, Zahedan, Iran
e-mail: mt_maghsoodlou@yahoo.com
K. Khandan-Barani
Department of Chemistry, Zahedan Branch, Islamic Azad University, Zahedan, Iran
A. C. Willis
Research School of Chemistry, Australian National University, Canberra, ACT 0200, Australia
123

M. T. Maghsoodlou et al.
Heterocycles are of immense importance not only biologically and industrially
but also because of their use of any developed human society [7]. Polysubstituted
furans are important in organic chemistry, because of their presence as key
structural units in many natural products [8] and important pharmaceuticals [9] and
also because of their use as building blocks in synthetic chemistry. Iminolactones
form one of the largest classical divisions of heterocyclic compounds. Iminolactones
can be hydrolyzed with aqueous hydrochloric acid to produce butenolides [10, 11]
(also named furan-2(5H)-ones) [12], an important class of biologically active
natural products used in medicine and agriculture [13–16].
Among the plethora of methods available for construction of heterocyclic
compounds, generation of 1,3-dipolar species and their trapping by suitable p
systems to produce five-membered heterocycles is extremely important, in large
measure because of the monumental contributions of Huisgen [17].
We and other chemists, for example Vijay Nair, have reported a series of
iminolactones prepared by reaction of isocyanide and activated acetylenic esters in
the presence of carbonyl compounds [18–22]. After our investigation of isocyanides
[23–26], we now report a novel one-pot synthesis of symmetric dialkyl 2,5-bis((2,6-
dimethylphenyl)imino)-2,5-dihydrofuran-3,4-dicarboxylate derivatives 4a–c by use
of 2,6-dimethyl phenylisocyanide 1 and 2,6-dimethyl phenylisocyanate 3 in the
presence of dialkyl acetylenedicarboxylates 2 as trapping agent for the reactive
zwitterionic intermediate. Recently, much attention has been devoted to multicom-
ponent reactions with isocyanates [27–29]. Organic isocyanates are powerful tools in
organic synthesis [30–32]. The important factor for the stability of the synthesized
compounds is high structural symmetry. This three-component condensation
reaction produces new symmetric compounds 4a–c in good yields (Scheme 1).
Unambiguous evidence for the structure of 4a was obtained from single crystal
X-ray analysis (Fig. 1).
Results and discussion
In our previous work we synthesized pyrrole derivatives under reflux conditions in
CH2Cl2 for 24–48 h [33]. Alizadeh et al. [34] have reported ethylenetetracarboxylic
acid derivatives as products in CH2Cl2 at room temperature. In this study, we used
2,6-dimethyl phenylisocyanide 1 and 2,6-dimethyl phenylisocyanate 3 in the
O
C
CO2
R
RO2
C
C
N
N
H3C
CH3
CO2
C
R
H3C
CH3
H3
C
CH3
N
N
CH2Cl2
r.t.
O
C
CO2
R
1
3
H3C
CH3
4a-c
2
R= Me, Et, t-Bu
Scheme 1 Synthesis of symmetric dialkyl 2,5-bis((2,6-dimethylphenyl)imino)-2,5-dihydrofuran-3,4-
dicarboxylate derivatives
123

A novel one-pot synthesis
Fig. 1 ORTEP diagram of 4a
presence of dialkyl acetylenedicarboxylates 2 to obtain symmetric furan derivatives
1
4a–c as stable solids. The structures of 4a–c were determined by IR, H NMR, and
13C NMR spectroscopy, MS, and HRMS; in addition the structure of 4a was
authenticated by X-ray single-crystal diffraction. The mass spectra of compounds
1
4a–c contained molecular ion (M?) peaks at appropriate m/z values. The H NMR
spectrum of compound 4a contained a singlet for the four methyl groups of the
phenyls at d = 2.04 ppm, a broad singlet for two methoxy groups at d = 3.99 ppm,
and a multiplet for the aromatic region at d = 6.86–6.96 ppm, in accordance with
the symmetric phenyl groups of isocyanide and isocyanate. The 13C NMR spectrum
of 4a contained nine distinct signals consistent with its proposed structure. The
characteristic signal resulting from the two symmetric imino carbons was identified
as a singlet at d = 143.6 ppm, and peaks from two symmetric carbonyl groups were
observed at d = 160.3 ppm. Partial assignments of these resonances are given in the
‘‘Experimental’’ section. The FT-IR spectrum of compound 4a contained strong
absorption at 1,747 and 1,722 cm-1, ascribed to the ester carbonyl groups, and at
1
1,689 cm-1 attributed to C=N. The H NMR and 13C NMR spectra of 4b and 4c
were similar to that of 4a; details are given in the ‘‘Experimental’’ section. Dimethyl
2,5-bis((2,6-dimethylphenyl)imino)-2,5-dihydrofuran-3,4-dicarboxylate 4a was
obtained as an orange powder. Its molecular formula, C24H24N2O5, was determined
123

M. T. Maghsoodlou et al.
on the basis of positive HRESIMS at m/z 443.1587 [M ? Na]? (calcd 443.1583)
1
and supported by H, 13C NMR, and IR spectra. Single crystals of compound 4a
were grown from dichloromethane–n-hexane (1:3) solution. The X-ray structure is
in agreement with the NMR data for symmetric bisiminofuran derivatives (Fig. 1).
On the basis of the well established chemistry of isocyanides [35, 36], it is
reasonable to assume that compounds 4a–c result from initial addition of 2,6-
dimethyl phenylisocyanides 1 to the dialkyl acetylenedicarboxylates 2 and
concomitant addition to 2,6-dimethyl phenylisocyanate 3 leading to intermediate
6. Cyclization of the latter leads to the highly functionalized symmetric dialkyl 2,5-
bis((2,6-dimethylphenyl)imino)-2,5-dihydrofuran-3,4-dicarboxylate derivatives 4a–
c (Scheme 2).
In conclusion, we have found a novel and efficient synthesis of symmetric dialkyl
2,5-bis((2,6-dimethylphenyl)imino)-2,5-dihydrofuran-3,4-dicarboxylate derivatives
from 2,6-dimethyl phenylisocyanide and dialkyl acetylenedicarboxylates in the
presence of 2,6-dimethyl phenylisocyanate at room temperature. This procedure has
the advantage that not only is the reaction performed under neutral conditions but
also the reactants can be mixed without any activation or modification.
C
O
RO2C
N
C
N
CO2R
H3C
CH3
H3C
CH3
C
CO2R
+
N
+
CO2R
1
3
2
5
RO2C
CO2R
N
4a-c
N
O
6
Scheme 2 Proposed mechanism for formation of compounds 4a–c
123

A novel one-pot synthesis
Experimental
2,6-Dimethyl phenylisocyanide, 2,6-dimethyl phenylisocyanate, and dialkyl acet-
ylenedicarboxylates were purchased from Fluka and Aldrich and used without
further purification. Melting points and IR spectra were measured on an
Electrothermal 9100 apparatus and a Jasco FT-IR spectrometer, respectively. The
1H and 13C NMR spectra were recorded on a Bruker DRX-400 Avance instrument
with CDCl3 as solvent at 400.1 and 100.6 MHz, respectively. Mass spectra were
recorded on a Shimadzu GC/MS QP 1100 EX mass spectrometer operating at an
ionization potential of 70 eV. High-resolution mass spectra (HRMS) were recorded
on a Waters LCT Premier XW (ESI-TOF MS) spectrometer at the Research School
of Chemistry, Australian National University, Canberra ACT 0200, Australia.
General procedure
The process for preparation of dialkyl 2,5-bis((2,6-dimethylphenyl)imino)-2,5-
dihydrofuran-3,4-dicarboxylate 4a is described as an example. A solution of 2,6-
dimethyl phenylisocyanide (1 mmol) in 3 mL CH2Cl2 was slowly (over 3 min)
added dropwise to a mixture of 2,6-dimethyl phenylisocyanate (1 mmol) and
dimethyl acetylenedicarboxylate (1 mmol) in 20 mL CH2Cl2 at room temperature.
After the addition, the solution was stirred for 24 h. The solvent was then removed
under reduced pressure, and the residue was washed with a cold 1:3 mixture of
diethyl ether and n-hexane (2 9 3 mL) to afford the pure product.
Dimethyl 2,5-bis((2,6-dimethylphenyl)imino)-2,5-dihydrofuran-3,4-dicarboxylate (4a)
Orange powder, yield 0.39 g (93%). M.p.: 187–189 °C; IR (KBr) (mmax, cm-1): 1,747
and 1,722 (C=O), 1,689 (C=N); 1H NMR (400.1 MHz, CDCl3): dH 2.04 (12H, s, 4CH3
of phenyl), 3.99 (6H, br s, 2OCH3), 6.86–6.96 (6H, m, 2Ar-H); 13C NMR (100.6 MHz,
CDCl3): dC 18.2 (4CH3), 53.5 (2OCH3), 124.6, 127.1, 127.7, 128.1, 130.1 (Carom and
C
olefin), 143.6 (2C=N), 160.3 (2C=O); MS, m/z (%) = 420 (M?, 20), 405 (6), 329(95),
268 (62), 121 (100), 105 (68), 77 (86); HRMS (ESI): m/z = [M ? Na]?calcd for
C24H24N2O5Na, 443.1583 found: 443.1587. X-ray data for compound 4a: empirical
formula, C24H24N2O5, formula weight = 420.46, T = 200 K, triclinic, space group =
˚
˚
˚
P 1; a = 7.7792(2) A, b = 9.9200(3) A, c = 14.6581(4) A, a = 85.8258(19)°,
3
-3
˚
b = 84.7935(19)°, c = 73.1651(15)°, V 1076.93(5) A , Dx = 1.297 gm cm
,
23,617 reflections measured (2h B 50°), 4,999 unique data, R = 0.045 (for 3,977
reflections with I [ 2r(I)], Rw = 0.116 (all data), S = 0.97. The crystallographic
information file has been deposited with the Cambridge Crystallographic Data Centre,
CCDC 851567 contains the supplementary crystallographic data for this compound.
Diethyl 2,5-bis((2,6-dimethylphenyl)imino)-2,5-dihydrofuran-3,4-dicarboxylate (4b)
Orange powder, yield 0.39 g (87 %). M.p.: 78–80 °C; IR (KBr) (mmax, cm-1): 1,736
1
and 1,719 (C=O), 1,676 (C=N); H NMR (400.1 MHz, CDCl3): dH 1.42 (6H, br s,
123

M. T. Maghsoodlou et al.
2CH3), 2.08 (12H, s, 4CH3 of phenyl), 4.48 (4H, br s, 2OCH2), 6.89–7.06 (6H, m,
2Ar-H); 13C NMR (100.6 MHz, CDCl3): dC 13.9 (2CH3), 18.2 (4CH3 of phenyl),
62.8 (2OCH2), 124.6, 127.1, 127.2, 127.7, 129.2 (Carom and Colefin), 141.1 (2C=N),
159.9 (2C=O); MS, m/z (%) = 448 (M?, 15), 403 (6), 329 (76), 282 (20), 121 (78),
105 (61), 77 (75), 43 (100); HRMS (ESI): m/z = [M ? Na]?calcd for
C26H28N2O5Na, 471.1896 found: 471.1889.
Di-t-butyl2,5-bis((2,6-dimethylphenyl)imino)-2,5-dihydrofuran-3,4-dicarboxylate(4c)
Orange powder, yield 0.43 g (85%). M.p.: 149–151 °C; IR (KBr) (mmax, cm-1):
1,739 and 1,725 (C=O), 1,685 (C=N); 1H NMR (400.1 MHz, CDCl3): dH 1.56 (18H,
s, 2C(CH3)3), 2.07 (12H, s, 4CH3 of phenyl), 6.87–6.97 (6H, m, 2Ar-H); 13C NMR
(100.6 MHz, CDCl3): dC 18.2 (4CH3 of phenyl), 28.1 (2C(CH3)3), 84.9
(2OC(CH3)3), 124.3, 125.1, 127.0, 127.6, 129.0 (Carom and Colefin), 143.1 (2C=N),
158.9 (2C=O); MS, m/z (%) = 504 (M?, 21), 375(18), 329 (41), 301 (7), 121 (85),
105 (38), 77 (21), 57 (100); HRMS (ESI): m/z = [M ? H]?calcd for C30H37N2O5,
505.2702; found: 505.2703.
Acknowledgments We are much obliged to the Research Council of the University of Sistan and
Baluchestan for financial support.
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