One-pot four-component synthesis of N2-alkyl-N 3-[2-(1,3,4-oxadiazol-2-yl)aryl]benzofuran-2,3-diamines

Article abstract of DOI:10.1002/hlca.201100403

A simple synthesis of N²-alkyl-N³-[2-(1,3,4- oxadiazol-2-yl)aryl]benzofuran-2,3-diamines 5 via a one-pot four-component reaction is described (Scheme 1). A mixture of N-(isocyanoimino) triphenylphosphorane (1), a 2-aminobenzoic acid

Full text of DOI:10.1002/hlca.201100403

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Helvetica Chimica Acta – Vol. 95 (2012)
One-Pot Four-Component Synthesis of N2-Alkyl-N3-[2-(1,3,4-oxadiazol-2-
yl)aryl]benzofuran-2,3-diamines
by Mehdi Adib*a), Ehsan Sheikhia), Morteza Karimzadeha), Hamid Reza Bijanzadehb), and
Massoud Amanlouc)
a) School of Chemistry, University College of Science, University of Tehran, P.O. Box 14155 – 6455,
Tehran, Iran (phone/fax: þ 98-21-66495291; e-mail: madib@khayam.ut.ac.ir)
b) Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
c) Pharmaceutical Sciences Research Center and Department of Medicinal Chemistry, Tehran University
of Medical Sciences, Tehran, Iran
A simple synthesis of N2-alkyl-N3-[2-(1,3,4-oxadiazol-2-yl)aryl]benzofuran-2,3-diamines 5 via a one-
pot four-component reaction is described (Scheme 1). A mixture of N-(isocyanoimino)triphenylphos-
phorane (1), a 2-aminobenzoic acid 2, a 2-hydroxybenzaldehyde 3, and an isocyanide 4 in absolute EtOH
at room temperature undergoes a smooth reaction to afford 5 in excellent yields (Table).
Introduction. – Multicomponent reactions (MCRs) have emerged as an efficient
and powerful tool in modern synthetic organic chemistry due to their valued features
such as atom economy, straightforward reaction design, and the opportunity to
construct target compounds by the introduction of several diversity elements in a single
chemical event. Typically, purification of products resulting from MCRs is also simple
since all the organic reagents employed are consumed and are incorporated into the
target compound [1]. MCRs, leading to interesting heterocyclic scaffolds, are
particularly useful for the construction of diverse chemical libraries of ꢀdrug-likeꢁ
molecules. The isocyanide-based MCRs are especially important in this area [1d][1e].
During recent years, there has been a broad investigation on different classes of
oxadiazoles. In particular, compounds containing the 1,3,4-oxadiazole moiety have
been shown to possess a wide range of pharmacological and therapeutic activities, e.g.,
as active inhibitors of several enzymes [2][3]. Furthermore, differently substituted
1,3,4-oxadiazoles have potential applications as photosensitizers [4], liquid crystals [5],
ionic liquids [6], and organic light-emitting devices [7]. Some examples have also
photomechanic [8], photoluminescent, and electrochromic properties [9][10]. So far,
the most common synthetic methods reported for the preparation of 1,3,4-oxadiazoles
involve either transformation of an existing heterocycle or cyclizations [2][3][11].
Benzofurans, another important class of heterocyclic compounds, have attracted
much attention because of their wide range of pharmaceutical activities [12].
Traditional synthetic routes for the preparation of benzofuran derivatives are often
multistep reactions such as dehydrative cyclization of a-(phenoxy)alkyl ketones [13],
cyclofragmentation of oxiranes [14], acidic dehydration of o-hydroxybenzyl ketones
[15], base mediated decarboxylation of (o-acylphenoxy)acetic acids and esters [16],
reaction of phenols with a-acyl sulfoxides [17], and Pd-catalyzed synthesis from o-
ethynylphenol or from o-iodophenols and terminal arylacetylenes [18][19].
ꢂ 2012 Verlag Helvetica Chimica Acta AG, Zꢃrich

Helvetica Chimica Acta – Vol. 95 (2012)
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Results and Discussion. – There are several reports on the use of (isocyanoimino)-
triphenylphosphorane (¼ N-(triphenylphosphoranylidene)isocyanamide; Ph3PNNC, 1;
Scheme 1) in syntheses of metal complexes [20]. Recently, syntheses of 1,3,4-
oxadiazepines [21a] and a variety of 1,3,4-oxadiazole derivatives [21] by using 1 in
MCRs were reported. As part of our current studies on the design of new routes for the
preparation of biologically active heterocyclic compounds from readily available
building blocks [22], we have described the syntheses of 2-aryl-5-(hydroxyalkyl)-1,3,4-
oxadiazoles [23a], 3-(1-hydroxyalkyl)[1,2,4]triazolo[4,3-c]quinazolines [23b], 3-(5-
aryl/alkyl-1,3,4-oxadiazol-2-yl)-1,3-dihydro-3-hydroxy-2H-indol-2-ones [23c], 3-aryl-1-
[(arylmethylidene)amino]pyrrolidine-2,5-diones [23d], and 3,4-disubstituted N-amino-
pyrrolidine-2,5-diones [23e] by using 1 in MCRs.
We report herein a simple synthesis of N3-[2-(1,3,4-oxadiazol-2-yl)aryl]benzofuran-
2,3-diamines 5 via a four-component reaction (Scheme 1). Thus, a mixture of 1, a 2-
aminobenzoic acid 2, a 2-hydroxybenzaldehyde 3, and an isocyanide 4 in absolute
EtOH underwent a smooth reaction to give the corresponding N2-alkyl-N3-[2-(1,3,4-
oxadiazol-2-yl)aryl]benzofuran-2,3-diamines 5a – 5g in 90 – 96% yield (Scheme 1,
Table). The reactions were carried out by first mixing 2, 3, and 4 in EtOH at room
temperature. After 1 h and nearly complete conversion to the corresponding
benzofuran-2,3-diamine intermediate (TLC monitoring), 1 was added to the mixture,
1
which was stirred at room temperature for further 2 h. The H-NMR spectra of the
crude products clearly indicated the formation of compounds 5 in excellent yields
(Table).
Scheme 1. One-Pot Four-Component Synthesis of N3-[2-(1,3,4-Oxadiazol-2-yl)aryl]benzofuran-2,3-di-
amines 5. See Table for X, Y, Z, and R.
Table. Synthesis of N2-Alkyl-N3-[2-(1,3,4-oxadiazol-2-yl)aryl]benzofuran-2,3-diamines 5a – 5g
Product
X
Y
Z
R
Yield [%]a)
5a
5b
5c
5d
5e
5f
5g
H
Cl
H
H
Cl
H
Cl
NO2
NO2
Br
H
Br
H
H
H
MeO
H
Me3CCH2C(Me)2
Me3CCH2C(Me)2
cyclohexyl
90
90
95
91
93
95
96
tBu
cyclohexyl
cyclohexyl
cyclohexyl
NO2
NO2
H
H
a) Yields of isolated product.

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Helvetica Chimica Acta – Vol. 95 (2012)
The isolated products 5 were characterized by their IR, 1H- and 13C-NMR, and mass
spectra and elemental analysis. The mass spectrum of 5b displayed the molecular-ion
(Mþ) peaks at m/z 485 and 483, which was consistent with a product formed from 2-
hydroxy-5-nitrobenzaldehyde, 2-amino-5-chlorobenzoic acid, 1,1,3,3-tetramethylbutyl
isocyanide, and (isocyanoimino)triphenylphosphorane in a 1:1:1:1 ratio with the loss
of H2O and Ph3PO. The IR spectrum of 5b showed absorptions at 3246 and 3128 cmꢀ1
indicative for NH of amine groups. The 1H-NMR spectrum of 5b exhibited four sharp s
arising from the Me3C (d(H) 0.98), Me2C (d(H) 1.48), and CH2 (d(H) 1.75) groups and
the oxadiazole-ring CH (d(H) 8.49), along with characteristic signals with appropriate
chemical shifts and coupling constants for the six aromatic H-atoms. Two fairly broad s
1
(d(H) 4.41 and 8.53) were observed for the two amine H-atoms. The H-decoupled
13C-NMR spectrum of 5b showed characteristic signals for the 1,1,3,3-tetramethylbutyl
group, two deshielded signals at d(C) 151.34 and 163.70 for the oxadiazole CH group
and C-atom, respectively, as well as 14 signals for the aromatic C atoms (6 CH and 8 C),
1
in agreement with the adduct structure (see Exper. Part). The H- and 13C-NMR
spectra of compounds 5a and 5c – 5g were similar to those of 5b, except for the signals
of the N2-alkyl and N3-aryl substituents and of the benzofuran moiety, which exhibited
characteristic signals with appropriate chemical shifts and coupling constants (see
Exper. Part).
A mechanistic rationalization for this reaction is provided in Scheme 2. On the basis
of the well-established chemistry of isocyanides [1d][1e][24 – 26], it is reasonable to
assume that the imino intermediate 6, generated from the condensation reaction
between a 2-aminobenzoic acid 2 and an aldehyde 3, could undergo nucleophilic
addition of the isocyanide 4, which is facilitated by protonation by the adjacent
carboxylic acid function, leading to a nitrilium carboxylate intermediate 7. The nitrilium
may then undergo intramolecular attack by the adjacent phenol OH group to form 3-
aminobenzofuran-2(3H)-imine derivative 8, which could tautomerize to give benzo-
furan-2,3-diamine derivative 9 [27]. This COOH-substituted intermediate may
protonate 1, and the nitrilium intermediate 11 may be attacked by the conjugate base
10 to form the adduct 12. This adduct may undergo an intramolecular aza-Wittig
reaction of the iminophosphorane moiety with the ester C¼O to form the 1,3,4-
oxadiazole ring by removal of Ph3P¼O from zwitterion 13 and afford the isolated
products 5 [21b – 21h][23a – 23c].
In summary, we have developed a one-pot four-component reaction between
(isocyanoimino)triphenylphosphorane (1), a 2-aminobenzoic acid 2, a 2-hydroxyben-
zaldehyde 3, and an isocyanide 4 for the preparation of N2-alkyl-N3-(2-(1,3,4-oxadiazol-
2-yl)aryl)benzofuran-2,3-diamines 5, which are of potential synthetic and pharmaco-
logical interest. Mild reaction conditions and excellent yields of the products are the
main advantages of this method. The reactions were performed under neutral
conditions, and the starting materials were mixed without any activation or
modification.
This research was supported by the Research Council of the University of Tehran (research project
No. 6102036/1/03).

Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 2. Proposed Mechanism for the MCR
791
Experimental Part
General. All the chemicals were obtained from Merck (Germany) and used without further
purification. Column chromatography (CC): silica gel 60 (SiO2; Merck). M.p.: Electrothermal-9100
.
apparatus; uncorrected. IR Spectra: Shimadzu-IR-460 spectrometer; ˜n in cmꢀ1 1H- and 13C-NMR
Spectra: Bruker-DRX-500-Avance (at 500.1 and 125.8 MHz, resp.) and Bruker-DRX-300 (at 300.1 and
75.5 MHz, resp.) instruments; in CDCl3; d in ppm rel. to Me4Si as internal standard, J in Hz. EI-MS
(20 eV): Agilent-Technologies (HP) 5973 mass spectrometer; in m/z (rel. %). Elemental analyses:
Heraeus-CHN-O-Rapid analyzer.
Compounds 5: General Procedure. Exemplified with 5a. A mixture of 2-aminobenzoic acid (2a;
0.137 g, 1 mmol), 2-hydroxy-5-nitrobenzaldehyde (3a; 0.167 g, 1 mmol), and 1,1,3,3-tetramethylbutyl
isocyanide (4a; 0.139 g, 1 mmol) in EtOH (2 ml) was stirred at 258 for 1 h. Next, (isocyanoimino)-
triphenylphosphorane (1; 0.302 g, 1 mmol) was added to the mixture, which was stirred at 258 for further
2 h. Then, the solvent was evaporated, and the residue purified by CC (SiO2, hexane/AcOEt 3 :1) and
recrystallization (hexane/AcOEt 1:1).
5-Nitro-N3-[2-(1,3,4-oxadiazol-2-yl)phenyl]-N2-(1,1,3,3-tetramethylbutyl)benzofuran-2,3-diamine
(5a): Yield 90%. Orange crystals. M.p. 179 – 1818. IR (KBr): 3245 and 3135 (NH), 1618, 1512, 1455, 1339,
1277, 1218, 1141, 1079, 1006, 946, 877, 824, 724. 1H-NMR (300.1 MHz): 1.00 (s, 9 H); 1.49 (s, 6 H); 1.75 (s,
2 H); 4.33 (br. s, 1 H); 6.64 (d, J ¼ 8.3, 1 H); 6.88 (dd, J ¼ 7.4, 7.7, 1 H); 7.29 (t, J ¼ 8.2, 1 H); 7.39 (d, J ¼ 8.8,
1 H); 7.88 (d, J ¼ 1.9, 1 H); 7.93 (d, J ¼ 7.9, 1 H); 7.97 (dd, J ¼ 1.9, 9.0, 1 H); 8.50 (s, 1 H); 8.55 (s, 1 H).
13C-NMR (75.5 MHz): 30.7; 31.5; 31.8; 54.1; 57.4; 95.2; 106.3; 110.2; 111.5; 113.3; 116.1; 117.7; 128.4;
129.0; 133.4; 144.5; 146.7; 151.1; 152.2; 157.7; 164.7. EI-MS: 449 (27, Mþ), 371 (9), 354 (6), 337 (100), 320
(77), 293 (17), 283 (2), 263 (6), 161 (11), 97 (7), 57 (43), 41 (18). Anal. calc. for C24H27N5O4 (449.51): C
64.13, H 6.05, N 15.58; found: C 64.09, H 6.03, N 15.52.

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N3-[4-Chloro-2-(1,3,4-oxadiazol-2-yl)phenyl]-5-nitro-N2-(1,1,3,3-tetramethylbutyl)benzofuran-2,3-
diamine (5b): Yield 90%. Orange crystals. M.p. 195 – 1978. IR (KBr): 3246 and 3128 (NH), 1634, 1580,
1491, 1385, 1338, 1302, 1252, 1208, 1135, 1078, 1009, 949, 875, 821, 736, 697. 1H-NMR (500.1 MHz,
CDCl3): 0.98 (s, 9 H); 1.48 (s, 6 H); 1.75 (s, 2 H); 4.41 (s, 1 H); 6.59 (d, J ¼ 9.0, 1 H); 7.22 (dd, J ¼ 2.5, 9.0,
1 H); 7.38 (d, J ¼ 8.9, 1 H); 7.83 (d, J ¼ 2.4, 1 H); 7.85 (d, J ¼ 2.4, 1 H); 7.95 (dd, J ¼ 2.4, 8.8, 1 H); 8.49 (s,
1 H); 8.53 (s, 1 H). 13C-NMR (125.8 MHz, CDCl3): 30.7; 31.5; 31.8; 54.1; 57.5; 94.5; 107.2; 110.2; 111.3;
114.9; 116.2; 122.5; 127.6; 128.9; 133.2; 144.6; 145.3; 151.3; 152.1; 157.7; 163.7. EI-MS: 485 (3, Mþ(37Cl)),
483 (9, Mþ(35Cl)), 452 (4), 371 (63), 354 (46), 343 (24), 327 (12), 267 (27), 236 (8), 165 (8), 149 (15), 137
(9), 121 (11), 111 (13), 97 (24), 83 (27), 69 (34), 57 (100), 43 (53). Anal. calc. for C24H26ClN5O4 (483.95):
C 59.56, H 5.42, N 14.47; found: C 59.47, H 5.44, N 14.36.
5-Bromo-N2-cyclohexyl-N3-[2-(1,3,4-oxadiazol-2-yl)phenyl]benzofuran-2,3-diamine (5c): Yield
95%. Yellow crystals. M.p. 184 – 1868. IR (KBr): 3323 and 3130 (NH), 1648, 1604, 1508, 1440, 1321,
1272, 1186, 1098, 1042, 996, 946, 852, 790, 739. 1H-NMR (500.1 MHz, CDCl3): 1.13 – 2.05 (m, 10 H);
3.59 – 3.63 (m, 1 H); 4.10 (br. s, 1 H); 6.70 (d, J ¼ 8.4, 1 H); 6.84 (t, J ¼ 8.1, 1 H); 7.09 (dd, J ¼ 2.0, 8.4,
1 H); 7.11 (d, J ¼ 1.9, 1 H); 7.15 (d, J ¼ 8.4, 1 H); 7.29 (dt, J ¼ 1.3, 8.4, 1 H); 7.88 (dd, J ¼ 1.3, 7.9, 1 H); 8.44
(s, 1 H); 8.46 (br. s, 1 H). 13C-NMR (125.8 MHz, CDCl3): 25.0; 25.5; 34.4; 52.6; 92.2; 105.9; 111.3; 113.6;
116.3; 117.2; 118.3; 122.4; 128.3; 131.2; 133.4; 147.1; 147.7; 151.0; 155.5; 164.8. EI-MS: 454 (66, Mþ(81Br)),
452 (65, Mþ(79Br)), 371 (42), 344 (23), 326 (28), 301 (18), 263 (9), 199 (49), 178 (12), 161 (48), 149 (40),
120 (26), 93 (18), 83 (93), 69 (44), 55 (100), 41 (77). Anal. calc. for C22H21BrN4O2 (453.34): C 58.29, H
4.67, N 12.36; found: C 58.21, H 4.57, N 12.14.
N2-(tert-Butyl)-7-methoxy-N3-[2-(1,3,4-oxadiazol-2-yl)phenyl]benzofuran-2,3-diamine (5d): Yield
91%. Yellow crystals. M.p. 2238. IR (KBr): 3315 and 3167 (NH), 1629, 1574, 1507, 1445, 1379, 1333,
1273, 1168, 1068, 950, 813, 717. 1H-NMR (500.1 MHz, CDCl3): 1.40 (s, 9 H); 3.88 (s, 1 H); 4.04 (s, 3 H);
6.67 (d, J ¼ 8.1, 1 H); 6.71 (d, J ¼ 7.7, 1 H); 6.75 (d, J ¼ 8.5, 1 H); 6.83 (t, J ¼ 7.7, 1 H); 7.02 (t, J ¼ 7.9, 1 H);
7.27 (t, J ¼ 7.7, 1 H); 7.89 (dd, J ¼ 1.3, 7.9, 1 H); 8.47 (s, 1 H); 8.58 (br. s, 1 H). 13C-NMR (125.8 MHz,
CDCl3): 30.5; 53.8; 56.4; 99.5; 105.3; 105.9; 109.7; 113.9; 117.1; 123.4; 128.2; 129.6; 133.2; 138.4; 144.6;
147.1; 151.0; 154.5; 164.8. EI-MS: 378 (<1, Mþ), 277 (100), 236 (8), 199 (15), 183 (10), 151 (17), 109 (12),
91 (8), 77 (14), 65 (5), 51 (11). Anal. calc. for C21H22N4O3 (378.43): C 66.65, H 5.86, N 14.81; found: C
66.60, H 5.78, N 14.74.
5-Bromo-N3-[4-chloro-2-(1,3,4-oxadiazol-2-yl)phenyl]-N2-cyclohexylbenzofuran-2,3-diamine (5e):
Yield 93%. Yellow crystals. M.p. 194 – 1968. IR (KBr): 3353 and 3142 (NH), 1640, 1611, 1579, 1501,
1476, 1444, 1396, 1308, 1264, 1229, 1193, 1170, 1108, 1042, 994, 950, 875, 851, 823, 783, 749, 728. 1H-NMR
(300.1 MHz, CDCl3): 1.13 – 2.06 (m, 10 H); 3.58 – 3.62 (m, 1 H); 4.07 (d, J ¼ 8.6, 1 H); 6.65 (d, J ¼ 9.0,
1 H); 7.07 – 7.15 (m, 2 H); 7.24 (dd, J ¼ 1.7, 9.1, 1 H); 7.27 (s, 1 H); 7.87 (d, J ¼ 1.9, 1 H); 8.46 (br. s, 1 H);
8.51 (s, 1 H). 13C-NMR (75.5 MHz, CDCl3): 24.9; 25.4; 34.4; 52.5; 91.6; 106.7; 111.4; 115.1; 116.3; 118.1;
121.9; 122.5; 127.4; 130.8; 133.2; 145.6; 147.5; 151.2; 155.4; 163.8. EI-MS: 490 (<1, Mþ(81Br37Cl)), 488 (3,
Mþ(81Br35Cl)/(79Br37Cl)), 486 (2, Mþ(79Br35Cl)), 405 (4), 390 (5), 335 (45), 317 (3), 195 (5), 180 (4), 171
(6), 111 (5), 69 (55), 57 (42), 43 (100). Anal. calc. for C22H20BrClN4O2 (487.78): C 54.17, H 4.13, N 11.49;
found: C 54.09, H 4.14, N 11.43.
N2-Cyclohexyl-5-nitro-N3-[2-(1,3,4-oxadiazol-2-yl)phenyl]benzofuran-2,3-diamine (5f): Yield 95%.
Orange crystals. M.p. 184 – 1868. IR (KBr): 3317 and 3139 (NH), 1652, 1582, 1512, 1442, 1333, 1276, 1196,
1
1157, 1099, 999, 948, 879, 820, 736. H-NMR (500.1 MHz, CDCl3): 1.14 – 2.06 (m, 10 H); 3.61 – 3.68 (m,
1 H); 3.69 (br. s, 1 H); 6.67 (d, J ¼ 8.5, 1 H); 6.86 (t, J ¼ 7.5, 1 H); 7.27 (t, J ¼ 7.3, 1 H); 7.33 (d, J ¼ 8.8,
1 H); 7.84 (d, J ¼ 2.0, 1 H); 7.90 (d, J ¼ 8.0, 1 H); 7.93 (dd, J ¼ 1.9, 8.8, 1 H); 8.47 (s, 1 H); 8.50 (br. s, 1 H).
13C-NMR (125.8 MHz, CDCl3): 24.9; 25.4; 34.4; 52.6; 92.4; 106.2; 109.9; 111.2; 113.3; 116.0; 117.6; 128.4;
130.1; 133.4; 144.6; 146.8; 151.1; 151.8; 157.0; 164.7. EI-MS: 419 (9, Mþ), 320 (9), 309 (4), 300 (100), 270
(4), 254 (32), 210 (5), 182 (12), 167 (10), 57 (11), 43 (11). Anal. calc. for C22H21N5O4 (419.44): C 63.00, H
5.05, N 16.70; found: C 62.81, H 5.24, N 16.58.
N3-[4-Chloro-2-(1,3,4-oxadiazol-2-yl)phenyl]-N2-cyclohexyl-5-nitrobenzofuran-2,3-diamine (5g):
Yield 96%. Orange crystals. M.p. 174 – 1768. IR (KBr): 3368 and 3136 (NH), 1651, 1590, 1512, 1474,
1390, 1336, 1232, 1164, 1097, 1044, 1000, 952, 876, 808, 742. 1H-NMR (500.1 MHz, CDCl3): 1.14 – 2.05 (m,
10 H); 3.62 – 3.67 (m, 1 H); 3.98 (br. s, 1 H); 6.61 (d, J ¼ 9.0, 1 H); 7.23 (dd, J ¼ 2.0, 8.9, 1 H); 7.33 (d, J ¼
8.8, 1 H); 7.82 (s, 1 H); 7.87 (s, 1 H); 7.94 (dd, J ¼ 2.0, 8.8, 1 H); 8.50 (s, 1 H); 8.52 (br. s, 1 H). 13C-NMR

Helvetica Chimica Acta – Vol. 95 (2012)
793
(125.8 MHz, CDCl3): 24.9; 25.4; 34.4; 52.6; 91.9; 107.1; 110.0; 111.1; 114.9; 116.1; 122.4; 127.7; 129.9;
133.3; 144.7; 145.4; 151.3; 151.8; 156.9; 164.7. EI-MS: 455 (5, Mþ(37Cl)), 453 (11, Mþ(35Cl)), 370 (5), 354
(7), 337 (6), 279 (8), 167 (19), 149 (57), 97 (17), 81 (33), 69 (74), 57 (61), 43 (100). Anal. calc. for
C22H20ClN5O4 (453.88): C 58.22, H 4.44, N 15.43; found: C 58.31, H 4.51, N 15.37.
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Received October 16, 2011