Three-component reaction of isocyanides and 2-formylbenzoic acid with dibenzylamine catalyzed by silica nanoparticles under solvent-free conditions

Article abstract of DOI:10.1002/hlca.201000124

Reaction of an isocyanide with an iminium ion intermediate, formed by reaction between 2-formylbenzoic acid and dibenzylamine in the presence of silica nanoparticles (silica NP, ca. 42 nm) proceeds smoothly at room temperature to afford isocoumarin (=1H-2

Full text of DOI:10.1002/hlca.201000124

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Three-Component Reaction of Isocyanides and 2-Formylbenzoic Acid with
Dibenzylamine Catalyzed by Silica Nanoparticles under Solvent-Free
Conditions
by Ali Ramazani* and Amir Mahyari
Chemistry Department, Zanjan University, P.O. Box 45195-313, Zanjan, Iran
(fax: þ 98-241-5283100; e-mail: aliramazani@gmail.com)
Reaction of an isocyanide with an iminium ion intermediate, formed by reaction between 2-
formylbenzoic acid and dibenzylamine in the presence of silica nanoparticles (silica NP, ca. 42 nm)
proceeds smoothly at room temperature to afford isocoumarin (¼1H-2-benzopyran-1-one) derivatives in
high yields (Scheme 1 and Table 1).
Introduction. – Recently, multicomponent condensation reactions have become
one of the most powerful methods for the synthesis of small-molecule libraries, due to
the fact that products are formed in a single step by simultaneous reactions of several
reagents, and the molecular diversity required for such combinatorial libraries can be
achieved by simply varying each component [1 – 6].
In recent years, nanoparticles (NP) have attracted tremendous attention in catalysis
because of their improved efficiency under mild and environmentally benign conditions
in the context of ecological (Green) synthesis [7][8]. Due to their enormously large
and highly reactive surface area, NP have potential to exhibit superior catalytic activity
in comparison to bulk counterparts [9][10].
In this article, we wish to report a simple and practical procedure for the
preparation of isocoumarin (¼1H-2-benzopyran-1-one) derivatives through a multi-
component condensation reaction (MCR) in the presence of silica nanoparticles (silica
NP, ca. 42 nm).
Results and Discussion. – As part of our ongoing program to develop efficient and
robust methods for the preparation of heterocyclic compounds [11 – 32], we report here
a simple, one-pot, three-component reaction between isocyanides 3, dibenzylamine (2),
and 2-formylbenzoic acid (1) in the presence of silica NP at room temperature, leading
after 5 h to isocoumarin derivatives 4 (Scheme 1 and Table 1).
Silica nanoparticles were prepared by thermal decomposition of rice hulls [33]. The
results from X-ray diffraction (XRD) showed that the sample was silica NP as
indicated by broadened peaks around 2q ¼ 228 (Fig. 1). The morphology and grain size
of the silica NP was investigated by scanning electron microscopy (SEM) (Fig. 2).
Silica NP were found to catalyze the synthesis of isocoumarin derivatives 4 from 2-
formylbenzoic acid (1), isocyanides (3), and dibenzylamine (2) under solvent-free
conditions with high efficiency (Table 1). We also used silica gel powder (Merck)
ꢀ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Scheme 1. Three-Component Synthesis of Isocoumarin Derivatives 4 in the Presence of Silica Nano-
particles (NP). See Table 1 for R.
Table 1. SiO2 NP-Promoted Synthesis of Isocoumarin Derivatives 4a)
4
R
Yield [%]b)
a
b
c
d
e
t-Bu
cyclohexyl
1,1,3,3-tetramethylbutyl
Bn
2,6-dimethylphenyl
97
94
97
96
70
a) See Scheme 1; 0.3 g of SiO2 NP/mmol reactants were applied. b) Yield of isolated 4.
Fig. 1. X-Ray diffraction pattern of the synthesized silica nanoparticles
instead of silica NP in this reaction, but increase of reaction times and decrease of
isocoumarin yields were observed (Table 2). The use of just 0.3 g of silica NP per mmol
of reactants was sufficient to push the reaction forward. Higher amounts of silica NP
(0.4 g) did not improve the result to a great extent (Table 2, Entries 5 – 7).

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Fig. 2. SEM of the synthesized silica nanoparticles
To investigate the effects of other reaction media in this reaction, we carried out the
described condensation of 1 – 3 in CH2Cl2, H2O, and solvent-free (neat) systems
without silica (Table 2, Entries 1 – 3). The reactions proceeded with dibenzylamine in
fairly low to moderate yields. We also used other secondary amines (diethylamine,
pipyridine, and benzyl(methyl)amine) instead of dibenzylamine in this reaction in the
presence of CH2Cl2, H2O, silica NP, and silica gel powder, and also in solvent-free and
catalyst-free (neat) systems, but in all cases, several products were observed (based on
TLC investigations). So, the reactions with other than dibenzylamine have no synthetic
value.

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Table 2. Synthesis of Isocoumarin 4a from 2-Formylbenzoic Acid, Dibenzylaminea), and tert-Butyl
Isocyanide under Various Conditions
Entry
Catalystb) or solvent
Temp [8]
Time [h]
Yield [%]c)
1
2
3
4
5
6
7
CH2Cl2
H2O
neat
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
12
12
12
12
5
30
57
35
47
88
97
97
silica gel powder (0.3 g; Merck)
SiO2 NP (0.2 g)
SiO2 NP (0.3 g)
SiO2 NP (0.4 g)
5
5
a) We also used other secondary amines (diethylamine, pipyridine, and benzyl(methyl)amine) instead of
dibenzylamine in these reactions, but in all cases, several products were observed (based on TLC
investigations). So, this reactions have no synthetic value. b) Amount of SiO2 catalyst per mmol of
reactants in parentheses. c) Yields of isolated 4a.
The structures of compounds 4a – 4e were deduced from their IR, 1H- and
13C-NMR, and mass spectra. For example, the IR spectrum (KBr) of 4a showed a
strong absorption at 3344 cmꢀ1 in accordance with the presence of an NH group in the
1
molecule. The H-NMR spectrum (CDCl3) of 4a consisted of a s for the Me groups
(Me3C, d(H) 1.08), an AB system for the two PhCH2 groups (d(H) 4.17 and 4.25,
2JAB ¼ 12.6 Hz), indicating strong intramolecular H-bonding in the molecule
(Scheme 1), an amine H-atom (d(H) 5.22) which was exchangeable with D2O, two
ms for the aromatic H-atoms (d(H) 7.06 – 7.34 and 7.43 – 7.64), and one d for HꢀC(8)
1
(d(H) 8.13 (3J ¼ 8.0 Hz)). The H-decoupled 13C-NMR spectrum of 4a showed 16
distinct resonances, the partial assignment of these resonances is given in the Exper.
Part. The 1H- and 13C-NMR spectra of compounds 4b – 4e were similar to those of 4a,
except for the aromatic moieties and the alkyl groups which exhibited characteristic
signals with appropriate chemical shifts.
Although we have not established the mechanism of the reaction in an
experimental manner, a plausible reaction sequence that accounts for the formation
of 4 is shown in Scheme 2. Thus, condensation of 2-formylbenzoic acid (1) and
dibenzylamine (2) would give the iminium ion intermediate 5, which would react with
the alkyl isocyanide 3 to afford intermediate 6. This intermediate would cyclize to
lactone 7. Tautomerization of 7 could then lead to the formation of the isocoumarin
derivatives 4.
It may be speculated that the polar amphoteric surface (OH groups of the silica NP)
facilitates the interaction of adsorbed weak acidic and basic components due to
stabilization of the corresponding transition states and intermediates by H-bonding.
This interaction with the neighboring silanol groups is shown in Scheme 2 for the first
reaction step. Participation of two proximate silanol groups (one as a H-bond donor
and the other as a H-bond acceptor) in the reaction mechanism also seems to be
plausible.
Conclusions. – We have developed an efficient route for the one-pot synthesis of
isocoumarin derivatives 4 from simple and readily available isocyanides 3, dibenzyl-

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Scheme 2. Proposed Mechanism for the Formation of Isocoumarins 4 in the Presence of Silica
Nanoparticles (NP)
amine (2), and 2-formylbenzoic acid (1) in the presence of silica NP. The ease of
workup and high yields of products make this procedure a useful tool of modern
synthetic methods.
This work was supported by the Zanjan University and the Iran National Science Foundation, INSF.
Experimental Part
General. Freshly distilled solvents were used throughout, and anh. solvents were dried according to
Perrin and Armarego [34]. IR Spectra (KBr): Mattson-1000 FT-IR spectrophotometer; KBr pellets; ˜n in
cmꢀ1. 1H- and 13C-NMR Spectra: Bruker-250 spectrometer; in CDCl3; d in ppm rel. to Me4Si as internal
standard, J in Hz. EI-MS: Finnigan-MAT-8430 mass spectrometer operating at an ionization potential of
20 eV; in m/z (rel. %). Elemental analyses: Heraeus-CHN-O-Rapid analyzer.
General Procedure. Silica nanoparticles (0.3 g) were added to a mixture of 2-formylbenzoic acid (1;
0.15 g, 1 mmol), dibenzylamine (2; 0.19 ml, 1 mmol), and tert-butyl isocyanide (2a; 0.12 ml, 1 mmol) at
r.t., followed by 5 h of stirring. After completion of the reaction, flash column chromatography
(petroleum ether/Et2O 10 :1) of the residue gave 4a.
3-[(tert-Butyl)amino]-4-(dibenzylamino)-1H-2-benzopyran-1-one (4a): Yellow oil. IR: 3340, 2963,
2
1751, 1673, 1475. 1H-NMR: 1.08 (s, Me3C); 4.17, 4.25 (AB, JAB ¼ 12.6, 2 PhCH2); 5.22 (br. s, NH,
exchanged by D2O); 7.06 – 7.34 (m, 2 C6H5); 7.43 – 7.64 (m, HꢀC(5), HꢀC(6), HꢀC(7)); 8.13 (d, 3J ¼ 8.0,
HꢀC(8)). 13C-NMR: 29.49 (Me3C); 51.40 (Me3CNH); 57.99 (2 PhCH2); 99.41, 114.54, 140.88, 157.39 (4 C
of isoc.); 119.60, 121.62, 131.09, 134.32 (4 CH of isoc.); 127.32, 128.37, 129.34 (10 CH of 2 Ph); 139.44
(2 Cipso of 2 Ph); 160.79 (C(1)¼O). EI-MS: 409 (5), 328 (13), 223 (54), 149 (19), 132 (15), 104 (24), 91
(100), 57 (19). Anal. calc. for C27H28N2O2: C 78.61, H 6.84, N 6.79; found: C 78.55, H 6.80, N 6.73.
3-(Cyclohexylamino)-4-(dibenzylamino)-1H-2-benzopyran-1-one (4b): Yellow oil. IR: 3407, 2930,
1738, 1615, 1484. 1H-NMR: 1.04 – 1.6 (2m, 5 CH2 of Chx); 3.28 – 3.32 (m, CHꢀN of Chx); 4.17, 4.25 (AB,
3
2JAB ¼ 12.7, 2 PhCH2); 4.96 (d, J ¼ 8.5, NH, exchanged by D2O); 7.06 – 7.35 (m, 2 C6H5); 7.41 – 7.63 (m,
HꢀC(5), HꢀC(6), HꢀC(7)); 8.12 (d, 3J ¼ 8.0, HꢀC(8)). 13C-NMR: 24.57 (2 CH2(b) of Chx); 25.44
(CH2(g) of Chx); 33.45 (2 CH2(a) of Chx); 49.32 (CHꢀN of Chx); 58.00 (2 PhCH2); 99.14, 114.65,
141.22, 157.35 (4 C of isoc.); 119.65, 121.57, 131.12, 134.41 (4 CH of isoc.); 127.30, 128.38, 129.26 (10 CH of
2 Ph); 139.44 (2 Cipso of 2 Ph); 161.02 (C(1) ¼O). EI-MS: 420 (5), 347 (7), 328 (6), 196 (11), 104 (11), 91
(100), 65 (7). Anal. calc. for C29H30N2O2: C 79.42, H 6.89, N 6.39; found: C 79.36, H 6.83, N 6.35.

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4-(Dibenzylamino)-3-[(1,1,3,3-tetramethylbutyl)amino]-1H-2-benzopyran-1-one (4c): Yellow oil.
1
IR: 3354, 2949, 1772, 1691, 1476. H-NMR: 0.86 (s, Me3C); 1.04 (s, C(Me)2NH); 1.52 (s, Me3CCH2);
4.17, 4.26 (AB, 2JAB ¼ 12.9, 2 PhCH2); 5.23 (s, NH, exchanged by D2O); 7.06 – 7.37 (m, 2 C6H5); 7.41 – 7.63
(m, HꢀC(5), HꢀC(6), HꢀC(7)); 8.14 (d, 3J ¼ 8.0, HꢀC(8)). 13C-NMR: 30.06 (C(Me)2NH); 31.38
(Me3C); 31.64 (Me3C); 52.53 (Me3CCH2); 55.22 (C(Me)2NH); 58.02 (2 PhCH2); 99.89, 114.40, 140.19,
157.30 (4 C of isoc.); 119.66, 121.54, 131.08, 134.27 (4 CH of isoc.); 127.38, 128.44, 129.33 (10 CH of 2 Ph);
139.41 (2 Cipso of 2 Ph); 160.63 (C(1)¼O of isoc.). EI-MS: 426 (2), 328 (5), 223 (63), 149 (52), 105 (16),
91 (100), 57 (41). Anal. calc. for C31H36N2O2: C 79.45, H 7.74, N 5.98; found: C 79.38, H 7.71, N 5.93.
3-(Benzylamino)-4-(dibenzylamino)-1H-2-benzopyran-1-one (4d): Yellow oil. IR: 3365, 2919, 1750,
1677, 1453. 1H-NMR: 4.02 (d, 3J ¼ 6.25, CH2NH); 4.22 (s, 2 PhCH2); 5.22 (t, 3J ¼ 6.2, NH, exchanged by
3
D2O); 7.02 – 7.32 (m, 3 C6H5); 7.39 – 7.64 (m, HꢀC(5), HꢀC(6), HꢀC(7)); 8.13 (d, J ¼ 8.0, HꢀC(8)).
13C-NMR: 45.40 (CH2NH); 57.95 (2 PhCH2); 100.11, 115.03, 140.92, 156.15 (4 C of isoc.); 120.02, 122.31,
131.17, 134.52 (4 CH of isoc.); 127.33, 127.36, 127.39, 128.37, 128.53, 129.17 (15 CH of 3 Ph); 139.44, 138.28
(3 C of 3 Ph); 160.74 (C(1)¼O of isoc.). EI-MS: 328 (16), 222 (41), 196 (15), 132 (6), 104 (12), 91 (100),
77 (5). Anal. calc. for C30H26N2O2: C 80.69, H 5.87, N 6.27; found: C 80.63, H 5.82, N 6.20.
4-(Dibenzylamino)-3-[(2,6-dimethylphenyl)amino]-1H-2-benzopyran-1-one (4e): Yellow oil. IR:
3357, 2915, 1743, 1644, 1465. 1H-NMR: 1.80 (s, 2 Me); 4.32, 4.39 (AB, 2JAB ¼ 13.0, 2 PhCH2); 5.61 (s, NH,
exchanged by D2O); 6.99 – 7.33 (2m, 13 arom. H); 7.42 – 7.64 (m, HꢀC(5), HꢀC(6), HꢀC(7)); 8.15 (d,
3J ¼ 8.2, HꢀC(8)). 13C-NMR: 18.18 (Me2C6H3); 57.96 (2 PhCH2); 99.81, 116.54, 139.09, 155.69 (4 C of
isoc.); 120.28, 122.48, 131.28, 134.47 (4 CH of isoc.); 120.12, 127.56, 128.16, 128.64, 129.27 (13 arom. CH);
126.66, 136.10, 138.44 (5 arom. C); 160.85 (C(1)¼O of isoc.). Anal. calc. for C31H28N2O2: C 80.84, H 6.13,
N 6.08; found: C 80.77, H 6.08, N 6.02.
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Received March 28, 2010