Synthesis of polysubstituted furans via a novel and efficient heterocyclization approach

Article abstract of DOI:10.1007/s11164-012-0518-9

A new catalyst-free, one-pot synthesis of polysubstituted furans is reported. A series of [4-(4-aryl)-5-(cyclohexylamino)-2-(pyridin-2-yl)furan-3- yl](pyridin-2-yl)-methanones was synthesized via multicomponent reaction of 1,3-di(pyridin-2-yl)propane-1,3-dione, aryl aldehydes, and cyclohexyl isocyanide. Springer Science+Business Media B.V. 2012.

Full text of DOI:10.1007/s11164-012-0518-9

Res Chem Intermed (2012) 38:1969–1974
DOI 10.1007/s11164-012-0518-9
Synthesis of polysubstituted furans via a novel
and efficient heterocyclization approach
•
Saman Damavandi Reza Sandaroos
Maral Pashirzad
•
Received: 23 August 2011 / Accepted: 22 February 2012 / Published online: 9 March 2012
Ó Springer Science+Business Media B.V. 2012
Abstract A new catalyst-free, one-pot synthesis of polysubstituted furans is reported.
A series of [4-(4-aryl)-5-(cyclohexylamino)-2-(pyridin-2-yl)furan-3-yl](pyridin-2-yl)-
methanones was synthesized via multicomponent reaction of 1,3-di(pyridin-2-yl)pro-
pane-1,3-dione, aryl aldehydes, and cyclohexyl isocyanide.
Keywords Polysubstituted furan Á Catalyst-free Á IMCR
Introduction
Multicomponent reactions (MCRs) include a series of simultaneous multi bond-
forming reactions which enable construction of structurally diverse compounds
through combinatorial interactions between simple starting materials, leading to the
target products by one-pot operation [1, 2]. Simplified purification of products
because of incorporation of all the starting substrates into the final product, and the
possibility of preparing complex products starting from simple initial substrates in
one-step operation, are other advantages of MCRs [3, 4].
Furans are important intermediates for synthesis of oxygenated natural products
[6]. Polysubstituted furans are among the most important heterocyclic compounds
with widespread occurrence in nature [5, 6]. The pharmacological and biological
S. Damavandi (&)
Department of Chemistry, Faculty of Sciences, University of Isfahan, 81746-73441 Isfahan, Iran
e-mail: saman_damavandi@yahoo.com
R. Sandaroos
Department of Chemistry, Faculty of Science, Birjand University, Birjand, Iran
M. Pashirzad
Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
e-mail: Mara_Pashirzad@yahoo.com
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S. Damavandi et al.
activities of furan derivatives have induced and encouraged a number of research
groups to introduce a wide spectrum of synthetic designs with the aim of obtaining
pharmacologically and biologically more active heterocyclic compounds [7–9].
Furthermore, many polysubstituted furans have been widely used as important
reaction intermediates in the total synthesis and synthetic industry.
Isocyanide-based MCRs (IMCRs), introduced in 1990s by Passerini and Ugi [10–
13], have attracted specific attention because of their high efficiency in synthesis of
various heterocyclic compounds. Consequently, many efforts have been devoted to
development of synthetic methods which allow rapid, efficient, and selective access
to the furan motif. Although structurally diverse furan derivatives have been
synthesized by applying isocyanide-based MCRs [14–21], to the best of our
knowledge, this synthetic plan has not been applied for synthesis of [4-(4-aryl)-5-
(cyclohexylamino)-2-(pyridin-2-yl)furan-3-yl](pyridin-2-yl)methanone derivatives.
As part of our continuing effort on the design of new routes for preparation of
heterocyclic compounds [22], in this study, we designed a one-pot synthesis for
preparation of fully substituted furans 4a–4i starting from 1,3-di(pyridin-2-
yl)propane-1,3-dione, aryl aldehydes, and cyclohexyl isocyanide (Scheme 1).
Results and discussion
Initially, the reaction of cyclohexyl isocyanide, benzaldehyde, and 1,3-di(pyridin-2-yl)-
propane-1,3-dione in C2H4Cl2 at reflux condition proceeded spontaneously, leading
to [5-(cyclohexylamino)-4-phenyl-2-(pyridin-2-yl)furan-3-yl](pyridin-2-yl)methanone
(4a) in good yield. The effect of solvent onthe mentioned reaction was then investigated
R
N
CHO
NC
O
O
O
N
N
C2H4Cl2
+
+
O
NH
6-8 h, Relux
R
N
4a-4i
Scheme 1 Multicomponent synthesis of polysubstituted furans
Table 1 Influence of solvent on the catalyst-free reaction of benzaldehyde, 1,3-di(pyridin-2-yl)propane-
1,3-dione, and cyclohexyl isocyanide
Solvent
C2H4Cl2
84
EtOH
70
CH3CN
78
CH2Cl2
68
DMF
80
THF
55
Yield (%)a,b
a
All reactions carried out at reflux condition for 8 h. Reaction conditions: benzaldehyde (1.0 equiv), 1,3-
diketone (1.0 equiv), cyclohexyl isocyanide (1.1 equiv)
b
Isolated yields
123

Synthesis of polysubstituted furans
1971
Table 2 Results of
Entrya
Ar
Product
Time (h)
Yield (%)a
multicomponent synthesis of
[4-(4-aryl)-5-(cyclohexylamino)-
2-(pyridin-2-yl)furan-3-
1
2
3
4
5
6
7
8
9
C6H5
4a
4b
4c
4d
4e
4f
6
84
90
90
87
86
84
82
80
80
4-NO2–C6H4
4-Cl–C6H4
4-Br–C6H4
4-CH3–C6H4
4-CH3O–C6H4
2-Cl–C6H4
2-NO2–C6H4
2-Br–C6H4
6
yl](pyridin-2-yl)methanones
6
6.5
7
7
4 g
4 h
4i
8
8
8
a
Yield of isolated products
toidentifythe most appropriate mediumforthisheterocyclizationreaction, withthe best
results being obtained in C2H4Cl2 (Table 1). Therefore, C2H4Cl2 was chosen as the
solvent for further synthesis. Under these optimized reaction conditions, a series of
[4-(4-aryl)-5-(cyclohexylamino)-2-(pyridin-2-yl)furan-3-yl](pyridin-2-yl)methanone
derivatives was synthesized with good yield. The results are summarized in Table 2.
The structure of products was determined on the basis of their elemental analysis,
mass spectrometry, nuclear magnetic resonance (NMR), and infrared (IR) spectral
data. The elucidation of the structure of 4f using spectral data is discussed as an
example. The 1H NMR spectrum of 4f consisted of multiplet signals for the
cyclohexyl rings (dH 1.12–2.15 ppm) and the N–CH resonance (dH 3.40) and a
sharp singlet for the methoxy group (dH 3.65 ppm). A broad resonance (dH
5.90 ppm) was observed for the NH group. The aromatic hydrogens give rise to
multiplet signals in the aromatic region of the spectrum. Furthermore, the protons
next to the nitrogen atom of the pyridine rings are deshielded (dH 8.65 and
8.85 ppm) since there is a lower electron density around them. Additionally, the
mass spectra of this compound displayed molecular ion peak at 543 m/z value.
The 13C NMR spectrum of 4f showed 24 distinct resonances in agreement with the
proposed structure. Four signals (d = 92.1, 111.3, 140.1, and 158.9 ppm) are
assigned to the furan carbon atoms. Also, aliphatic carbons could be carefully
assigned in the range d 20.6–52.1 ppm. Moreover, the elemental analysis data were
in good accordance with the calculated data.
The scope and limitations of the reaction with respect to the aldehyde component
were examined, and the results are presented in Table 2. It was determined that
substituted aromatic aldehydes containing electron-withdrawing groups and elec-
tron-donating groups tolerate the reaction conditions with good yields.
A reasonable mechanism for the synthesis of polysubstituted furans is depicted in
Scheme 2. The mechanism may involve initial formation of a conjugated electron-
deficient heterodyne intermediate by Knoevenagel condensation of the 1,3-
diketones and the aromatic aldehyde (1) followed by a Michael-type addition
reaction with cyclohexyl isocyanide to afford an iminolactone 2, which then
isomerizes to furnish the product 3 (Scheme 2). Presumably, the isomerization of 2
123

1972
S. Damavandi et al.
C
N
Ar
O
HO
H
O
N
CH
O
N
N
N
-H2O
N
N
N
O
O
O
Ar
C
N
Ar
Ar
H
O
O
N
O
O
N
N
O
N
O
N
N
Ar
O
N
N
N
N
O
NH
2
3
1
Scheme 2 The proposed mechanism for the catalyst-free synthesis of polysubstituted furans
to 3 is driven by the stability of the fully conjugated aminofuran heteroaromatic
moiety.
Conclusions
A novel and catalyst-free synthetic pathway to synthesize a series of [4-(4-aryl)-5-
(cyclohexylamino)-2-(pyridin-2-yl)furan-3-yl](pyridin-2-yl)methanones by one-pot
cyclocondensation of 1,3-di(pyridin-2-yl)propane-1,3-dione, aryl aldehydes, and
cyclohexyl isocyanide is described.
Experimental
A mixture of an aldehyde (1 mmol), 1,3-diphenylpropane-1,3-dione (1 mmol), and
cyclohexyl isocyanide (1.1 mmol) in C2H4Cl2 (5 mL) was stirred at reflux condition
for appropriate time. The progress of the reactions was monitored by thin-layer
chromatography (TLC, ethylacetate:n-hexane 1:5). After cooling to room temper-
ature, the resulting precipitate was filtered and chromatographed on silica gel,
eluting by ethylacetate:n-hexane 1:5 to obtain the desired pure product. The spectral
data of the selected products are as follows:
[5-(Cyclohexylamino)-4-phenyl-2-(pyridin-2-yl)furan-3-yl](pyridin-2-yl)meth-
1
anone (4a) FT-IR (mmax, cm-1): 3335 (N–H), 1655 (C=O); H NMR (250 MHz,
CDCl3): d 1.20–2.10 (10H, m, 5CH2), 3.44 (1H, m, N–CH), 5.45 (1H, s, NH),
7.25–7.55 (9H, m, Ar), 7.70–8.45 (4H, m, Ar). 13C NMR (75 MHz, CDCl3): 21.5,
26.2, 30.5, 52.6, 95.6, 112.8, 124.9, 119.4, 122.6, 125.7, 127.3, 128.0, 128.3,
129.5,129.9, 136.2, 137.1, 139.3, 148.3, 150.9, 155.2, 160.7, 180.5. EIMS (m/z): 423
(M?). Anal. Calcd. for C27H25N3O2: C, 76.57; H, 5.95; N, 9.92; Found: C, 76.23;
H, 5.89; N, 9.87.
123

Synthesis of polysubstituted furans
1973
[5-(Cyclohexylamino)-4-(4-nitrophenyl)-2-(pyridin-2-yl)furan-3-yl](pyridin-2-yl)-
methanone (4b) FT-IR (mmax, cm-1): 3325 (N–H), 1650 (C=O), 1320 and 1510
1
(NO2); H NMR (250 MHz, CDCl3): d 1.15–2.15 (10H, m, 5CH2), 3.35 (1H, m,
N–CH), 5.70 (1H, s, NH), 7.20–7.55 (3H, m, Ar), 7.60–7.95 (4H, m, Ar), 8.05–8.45
(3H, m, Ar), 8.70–8.82 (2H, m, Ar). EIMS (m/z): 468 (M?). Anal. Calcd. for
C27H24N4O4: C, 69.22; H, 5.16; N, 11.96; Found: C, 68.77; H, 5.11; N, 11.90.
[4-(4-Bromophenyl)-5-(cyclohexylamino)-2-(pyridin-2-yl)furan-3-yl](pyridin-2-yl)-
methanone (4d) FT-IR (mmax, cm-1): 3220 (N–H), 1635 (C=O); 1H NMR
(250 MHz, CDCl3): d 1.15–2.20 (10H, m, 5CH2), 3.53 (1H, m, N–CH), 6.15 (1H,
s, NH), 7.25–7.75 (7H, m, Ar), 7.80–8.25 (3H, m, Ar), 8.60–8.80 (2H, m, Ar). EIMS
(m/z): 501 (M?). Anal. Calcd. for C27H24BrN3O2: C, 64.55; H, 4.81; N, 8.36;
Found: C, 64.13; H, 4.77; N, 8.30.
[5-(Cyclohexylamino)-4-(4-methoxyphenyl)-2-(pyridin-2-yl)furan-3-yl](pyridin-
2-yl)methanone (4f) FT-IR (mmax, cm-1): 3312 (N–H), 1660 (C=O); 1H NMR
(250 MHz, CDCl3): d 1.12–2.15 (10H, m), 3.40 (1H, m, N–CH), 3.65 (3H, s, OMe),
5.90 (1H, s, NH), 6.90–7.38 (6H, m, Ar), 7.50–7.83 (4H, m, Ar), 8.65 (1H, m, Ar),
8.85 (1H, m, Ar). 13C NMR (75 MHz, CDCl3): 20.6, 25.4, 30.1, 52.1, 92.1, 111.3,
118.8, 119.4, 122.6, 124.4, 126.1, 126.9, 128.3, 129.5,129.9, 135.5, 135.9, 140.1,
147.8, 149.1, 153.2, 158.9, 169.8. EIMS (m/z): 543 (M?). Anal. Calcd. for
C28H27N3O3: C, 74.15; H, 6.00; N, 9.27; Found: C, 74.01; H, 5.93; N, 9.20.
[4-(2-Chlorophenyl)-5-(cyclohexylamino)-2-(pyridin-2-yl)furan-3-yl](pyridin-2-yl)-
methanone (4h) FT-IR (mmax, cm-1): 3335 (N–H), 1657 (C=O); 1H NMR
(250 MHz, CDCl3): d 1.15–2.20 (10H, m), 3.12 (1H, m, N–CH), 4.85 (1H, s,
NH), 7.20–7.57 (6H, m, Ar), 7.70–7.85 (3H, m, Ar), 7.90–8.45 (3H, m, Ar). EIMS
(m/z): 457 (M?). Anal. Calcd. for C27H24ClN3O2: C, 70.81; H, 5.28; N, 9.18;
Found: C, 70.22; H, 5.17; N, 9.11.
2-Benzylidene-1,3-di(pyridin-2-yl)propane-1,3-dione [intermediate (1)]: 1H
NMR (250 MHz, CDCl3): d 6.95 (s, 1H), 7.35–7.75 (m, 5H), 7.80–8.25 (m, 5H),
8.85 (m, 2H). 13C NMR (75 MHz, CDCl3): d 122.5, 127.5, 128.3, 129.8, 131.5,
134.0, 136.6, 138.1, 148.9, 154.2, 156.5, 188.7. EIMS (m/z): 314 (M?). Anal.
Calcd. for C20H14N2O2: C, 76.42; H, 4.49; N, 8.91; Found: C, 76.24; H, 4.54; N,
8.96.
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