Facile one-pot three-component synthesis of functionalized pyridylfuran-2-amines

Article abstract of DOI:10.1002/hlca.200690034

The reactive 1:1 zwitterionic intermediates generated in situ from the reaction between a series of isocyanides and diaroylacetylenes were trapped by pyridine carbaldehydes to yield highly functionalized 5-pyridylfuran-2-amines in good yields (82-93%).

Full text of DOI:10.1002/hlca.200690034

Helvetica Chimica Acta – Vol. 89 (2006)
299
Facile One-Pot Three-Component Synthesis of Functionalized Pyridylfuran-2-
amines
by Mehdi Adib*a), Mohammad Hosein Sayahia), Somayeh Aali Koloogania), and Peiman Mirzaeib)
a) School of Chemistry, University College of Science, University of Tehran, P.O. Box 14155-6455, Tehran,
Iran (phone/fax: +98-21-66495291; e-mail: madib@khayam.ut.ac.ir)
b) Department of Chemistry, Shahid Beheshti University, Tehran, Iran
The reactive 1:1 zwitterionic intermediates generated in situ from the reaction between a series of
isocyanides and diaroylacetylenes were trapped by pyridine carbaldehydes to yield highly functionalized
5-pyridylfuran-2-amines in good yields (82–93%).
Introduction. – Polysubstituted furans play an important role in organic chemistry,
not only due to their presence as key structural units in many natural products [1] and in
pharmaceuticals [2], but also because they are often used as building blocks in synthetic
chemistry. For this reason, the synthesis of polysubstituted furans continues to attract
the interest of many organic chemists.
Until now, only few papers dealing with the synthesis of furylpyridines have been
published [3–7]. As part of our current studies on the development of new routes in
heterocyclic chemistry [8–11], we now wish to report a facile one-pot three-component
synthesis of polyfunctional 5-pyridylfuran-2-amines.
Results and Discussion. – We have synthesized a series of furylpiperidines by the
ready 1:1:1 condensation of the isocyanides 1, the diaroylacetylenes (=1,4-diaryl-
but-2-yne-1,4-diones) 2, and the pyridine carbaldehydes 3 in CH2Cl2 at ambient temper-
ature. As can be seen from the Table, the resulting furylpyridines 4 were obtained in
82–93% yield. The reactions were carried out by first mixing the pyridine carbaldehyde
and the diaroylacetylene, before the isocyanide was added slowly. The reactions pro-
ceeded spontaneously in CH2Cl2, and were all complete within 12 h.
1
Compounds 4 were identified on the basis of elemental analyses, IR, H- and 13C-
NMR, and MS data. The mass spectrum of 4a displayed the M+ signal at m/z 450, in
1
accord with a 1:1:1 adduct. Its H-NMR spectrum exhibited characteristic signals at
d(H) 1.35–2.25 (series of m) for the five CH2 groups of the cyclohexyl moiety, and a
symmetric multiplet at d(H) 4.04 for the cyclohexyl methine H-atom, along with char-
acteristic aromatic signals at d(H) 7.04–8.36. The NH H-atom was observed at d(H)
3
8.56 (d, J=8.0 Hz) due to vicinal coupling with the cyclohexyl methine group. The
1H-decoupled 13C-NMR spectrum of 4a showed 23 distinct resonances, in agreement
with the proposed structure. Partial assignment of these resonances are given in the
1
Exper. Part. The H- and 13C-NMR spectra of compounds 4b–h were similar to those
of 4a, except for the signals of the aryl substituents, the alkylamino moieties, and the
© 2006 Verlag Helvetica Chimica Acta AG, Zürich

300
Helvetica Chimica Acta – Vol. 89 (2006)
Table. Syntheses and Structures a Series of Functionalized Pyridylfurans
Series
R
Ar
R’
Yield of 4 [%]a)
a
b
c
d
e
f
C6H11
C6H11
C6H11
C6H11
t-Bu
t-Bu
t-Bu
t-Bu
C6H5
C6H5
2,5-Me2ÀC6H3
2,5-Me2ÀC6H3
C6H5
2-CHO
4-CHO
2-CHO
4-CHO
2-CHO
4-CHO
2-CHO
4-CHO
93
92
86
83
87
89
91
82
C6H5
g
h
2,5-Me2ÀC6H3
2,5-Me2ÀC6H3
a) Isolated yield.
pyridine rings, which exhibited characteristic signals with appropriate chemical shifts
and coupling constants.
On the basis of the well-established chemistry of isocyanides [12–15], it is reason-
able to assume that the furylpyridines 4 result from initial addition of the isocyanide to
the unsaturated diketone, followed by nucleophilic attack of the 1:1 adduct 5 on the
aldehyde under formation of the 1:1:1 adducts 6. Next, intramolecular cyclization
by attack of the alkoxide to the nitrilium moiety yields the intermediate g-iminolactone
7, which finally isomerizes to 4 (Scheme).
Scheme
In summary, the present method has the advantage that the reaction can be per-
formed under neutral conditions, and that the substances can be mixed without prior
activation or modification. The simplicity of our synthetic protocol makes it an interest-
ing alternative to multistep approaches [3–7], and allows the ready preparation of

Helvetica Chimica Acta – Vol. 89 (2006)
301
highly functionalized pyridylfurans of potential synthetic and pharmaceutical interest
(see, e.g., [16–19]).
Experimental Part
General. tert-Butyl isocyanide, cyclohexyl isocyanide, and pyridine carbaldehydes were obtained
from Merck (Germany) and Fluka (Switzerland), and were used without further purification. Diaroyl-
acetylenes 2 were prepared according to literature procedures [20]. Column chromatography (CC): silica
gel 60 (Merck). Melting points (M.p.): Electrothermal 9100 apparatus; uncorrected. IR spectra: Shimadzu
1
IR-460 spectrometer; in cmÀ1. H- and 13C-NMR Spectra: Bruker DRX-500 AVANCE instrument; at
500.1 and 125.8 MHz, resp., in CDCl3; d in ppm rel. to Me4Si (=0 ppm), J in Hz. EI-MS (20 eV): Finnigan
MAT-8430 mass spectrometer; in m/z (rel. %). Elemental analyses: Heraeus CHN-O-Rapid analyzer.
General Procedure for the Preparation of Compounds 4. To a magnetically stirred soln. of 2 (1 mmol)
and 3 (107 mg, 1 mmol) in CH2Cl2 (6 ml) was added dropwise a soln. of 1 (1 mmol) in CH2Cl2 (2 ml) at
À58 over 10 min. The mixture was allowed to warm to r.t., and was stirred for 12 h. The solvent was
removed, and the residue was purified by CC (SiO2; hexane/AcOEt 2 :1) and recrystallization from hex-
ane/AcOEt 1:1.
[2-(Cyclohexylamino)-5-(pyridin-2-yl)furan-3,4-diyl]bis(phenylmethanone) (4a). Yield: 93%. Yel-
low crystals. M.p. 138–1398. IR (KBr): 3270 (NH), 1676, 1630 (C=O), 1542, 1464, 1404, 1229, 893,
692. 1H-NMR (500 MHz, CDCl3): 1.35–2.25 (m, 10 H); 4.04 (m, 1 H); 7.04 (t, J=6.9, 1 H); 7.07 (t,
J=7.6, 2 H); 7.18–7.25 (m, 5 H); 7.40 (t, J=7.4, 1 H); 7.55 (d, J=7.5, 2 H); 7.58 (d, J=8.0, 1 H); 7.65
(t, J=7.4, 1 H); 8.36 (d, J=3.3, 1 H); 8.56 (d, J=8.0, 1 H). 13C-NMR (125 MHz, CDCl3): 24.44; 25.37;
33.28; 51.41; 100.13; 119.20; 121.52; 122.88; 127.15; 127.65; 127.87; 128.89; 130.07; 132.57; 136.24;
137.57; 140.34; 140.69; 147.81; 149.34; 163.10; 190.18; 191.84. EI-MS: 451 (27, [M+1]+), 450 (7, M+),
383 (23), 368 (23), 325 (40), 264 (39), 236 (25), 205 (23), 105 (100), 77 (33), 27 (32). Anal. calc. for
C29H26N2O3 (450.54): C 77.31, H 5.82, N 6.22; found: C 77.3, H 5.8, N 6.3.
[2-(Cyclohexylamino)-5-(pyridin-4-yl)furan-3,4-diyl]bis(phenylmethanone) (4b). Yield: 92%. Yel-
low crystals. M.p. 114–1158. IR (KBr): 3265 (NH), 1670, 1634 (C=O), 1593, 1554, 1460, 1404, 1336,
1
1234, 1045, 889, 692. H-NMR (500 MHz, CDCl3): 1.29–2.20 (m, 10 H); 3.93 (m, 1 H); 7.06 (t, J=7.6,
2 H); 7.13 (d, J=7.0, 2 H); 7.17 (t, J=7.5, 2 H); 7.22 (t, J=7.3, 1 H); 7.37 (t, J=7.4, 1 H); 7.38–7.43
(m, 4 H); 8.39 (d, J=7.9, 1 H); 8.50 (d, J=6.0, 2 H). 13C-NMR (125 MHz, CDCl3): 24.43; 25.30; 33.20;
51.70; 100.40; 118.50; 124.32; 127.12; 127.84; 128.12; 128.79; 130.43; 133.26; 136.22; 137.08; 139.24;
140.27; 149.77; 162.56; 190.06; 192.06. EI-MS: 450 (33, M+), 406 (22), 105 (100), 77 (20), 55 (41), 40
(25), 29 (30). Anal. calc. for C29H26N2O3 (450.54): C 77.31, H 5.82, N 6.22; found: C 77.4, H 5.7, N 6.2.
[2-(Cyclohexylamino)-5-(pyridin-2-yl)furan-3,4-diyl]bis[(2,5-dimethylphenyl)methanone]
(4c).
Yield: 86%. Yellow crystals. M.p. 153–1548. IR (KBr): 3288 (NH), 1670, 1632 (C=O), 1547, 1468,
1342, 1282, 1040, 772. 1H-NMR (500 MHz, CDCl3): 1.30–1.90 (m, 8 H); 2.04 (s, 3 H); 2.05 (s, 3 H);
2.18–2.22 (m, 2 H); 2.24 (s, 3 H); 2.25 (s, 3 H); 4.02 (m, 1 H); 6.75 (s, 1 H); 6.79 (d, J=7.7, 1 H); 6.86
(d, J=7.6, 1 H); 6.94 (d, J=7.7, 1 H); 6.99 (dd, J=4.5, 6.2, 1 H); 7.08 (d, J=7.6, 1 H); 7.34 (s, 1 H);
7.51 (d, J=8.0, 1 H); 7.59 (t, J=7.9, 1 H); 8.35 (d, J=4.1, 1 H); 8.58 (d, J=6.8, 1 H). 13C-NMR (125
MHz, CDCl3): 18.51; 20.51; 20.76; 21.44; 24.54; 25.11; 33.32; 51.49; 101.02; 118.97; 121.24; 124.90;
127.60; 129.64; 129.92; 131.64; 131.69; 132.59; 132.95; 134.26; 134.36; 135.36; 136.18; 137.67; 139.77;
140.03; 148.00; 149.36; 162.80; 191.61; 192.45. EI-MS: 507 (30, [M+1]+), 506 (10, M+), 410 (25), 374
(20), 353 (31), 324 (17), 304 (33), 275 (28), 248 (17), 219 (12), 133 (100), 105 (68), 77 (27), 55 (18), 29
(31). Anal. calc. for C33H34N2O3 (506.64): C 78.23, H 6.76, N 5.53; found: C 78.3, H 6.8, N 5.3.
[2-(Cyclohexylamino)-5-(pyridin-4-yl)furan-3,4-diyl]bis[(2,5-dimethylphenyl)methanone]
(4d).
Yield: 83%. Yellow crystals. M.p. 97–1018. IR (KBr): 3287 (NH), 1665, 1634 (C=O), 1597, 1549, 1466,
1337, 1172, 1038, 813, 731. 1H-NMR (500 MHz, CDCl3): 1.17–1.77 (m, 8 H); 1.80 (s, 3 H); 1.94 (s, 3
H); 2.01 (s, 3 H); 2.02–2.09 (m, 2 H); 2.10 (s, 3 H); 3.80 (m, 1 H); 6.56 (d, J=1.2, 1 H); 6.60 (d,
J=7.7, 1 H); 6.71 (dd, J=1.2, 7.6, 1 H); 6.79 (d, J=7.7, 1 H); 6.97 (dd, J=1.1, 8.1, 1 H); 7.13 (d,
J=1.1, 1 H); 7.19 (d, J=5.9, 2 H); 8.33 (d, J=5.9, 2 H); 8.35 (d, J=7.5, 1 H). 13C-NMR (125.8 MHz,
CDCl3): 18.45; 20.55; 20.65; 21.45; 24.48; 25.31; 33.17; 51.71; 101.21; 118.10; 126.04; 127.55; 129.97;

302
Helvetica Chimica Acta – Vol. 89 (2006)
130.13; 131.81; 132.12; 132.89; 133.41; 134.41; 134.63; 134.89; 136.29; 138.04; 138.35; 139.58; 149.82;
162.42; 191.37; 192.82. EI-MS: 506 (82, M+), 491 (15), 409 (38), 373 (15), 291 (8), 133 (100), 105 (50),
84 (20), 55 (22), 41 (11), 29 (4). Anal. calc. for C33H34N2O3 (506.64): C 78.23, H 6.76, N 5.53; found: C
78.3, H 6.9, N 5.4.
{2-[(1,1-Dimethylethyl)amino]-5-(pyridin-2-yl)furan-3,4-diyl}bis[phenylmethanone] (4e). Yield:
87%. Yellow crystals. M.p. 170–1728. IR (KBr): 3263 (NH), 1678, 1628 (C=O), 1551, 1465, 1373, 1225,
1
951, 692. H-NMR (500 MHz, CDCl3): 1.65 (s, 9 H); 6.98 (dd, J=4.9, 6.1, 1 H); 7.04 (t, J=7.7, 2 H);
7.17–7.23 (m, 5 H); 7.37 (t, J=7.4, 1 H); 7.55 (d, J=7.6, 2 H); 7.57 (d, J=7.5, 1 H); 7.62 (t, J=7.7, 1
H); 8.25 (d, J=4.4, 1 H); 8.88 (s, 1 H). 13C-NMR (125 MHz, CDCl3): 29.72; 53.12; 100.85; 118.73;
121.44; 122.48; 127.15; 127.64; 127.87; 128.91; 130.07; 132.58; 136.32; 137.57; 140.31; 140.98; 147.82;
149.38; 163.32; 190.31; 191.87. EI-MS: 425 (37, M+), 368 (13), 350 (47), 322 (32), 291 (16), 246 (22),
105 (100), 77 (78), 57 (40), 41 (26), 28 (61). Anal. calc. for C27H24N2O3 (424.50): C 76.40, H 5.70, N
6.60; found: C 76.3, H 5.8, N 6.5.
{2-[(1,1-Dimethylethyl)amino]-5-(pyridin-4-yl)furan-3,4-diyl}bis[phenylmethanone] (4f). Yield:
89%. Yellow crystals. M.p. 125–1298. IR (KBr): 3271 (NH), 1660, 1630 (C=O), 1589, 1547, 1456, 1373,
1225, 1069, 950, 820, 696. 1H-NMR (500 MHz, CDCl3): 1.62 (s, 9 H); 7.00–7.18 (m, 6 H); 7.22 (t,
J=7.0, 1 H); 7.33–7.42 (m, 5 H); 8.49 (d, J=6.2, 2 H); 8.67 (s, 1 H). 13C-NMR (125 MHz, CDCl3):
28.71; 52.27; 100.03; 117.48; 122.80; 126.15; 126.90; 127.16; 127.82; 129.51; 132.34; 135.01; 136.06;
138.85; 139.25; 149.17; 161.75; 189.23; 191.28. EI-MS: 424 (60, M+), 383 (38), 367 (100), 350 (11), 301
(22), 105 (20), 71 (73), 57 (67), 41 (44), 29 (26). Anal. calc. for C27H24N2O3 (424.50): C 76.40, H 5.70, N
6.60; found: C 76.4, H 5.6, N 6.6.
{2-[(1,1-Dimethylethyl)amino]-5-(pyridin-2-yl)furan-3,4-diyl}bis[(2,5-dimethylphenyl)methanone]
(4g). Yield: 91%. Yellow crystals. M.p. 111–1148. IR (KBr): 3298 (NH), 1674, 1626 (C=O), 1551, 1463,
1373, 1265, 1207, 1175, 1105, 960, 789. 1H-NMR (500 MHz, CDCl3): 1.64 (s, 9 H); 2.01 (s, 3 H); 2.02 (s, 3
H); 2.21 (s, 3 H); 2.23 (s, 3 H); 6.71 (d, J=1.2, 1 H); 6.75 (d, J=7.7, 1 H); 6.83 (dd, J=1.6, 7.6, 1 H); 6.91
(d, J=7.7, 1 H); 6.96 (dd, J=1.1, 7.4, 1 H); 7.05 (dd, J=1.4, 7.7, 1 H); 7.32 (d, J=1.2, 1 H); 7.50 (d, J=8.0,
1 H); 7.59 (dt, J=1.7, 7.5, 1 H); 8.28 (dd, J=1.1, J=4.9, 1 H); 8.85 (s, 1 H). 13C-NMR (125.8 MHz,
CDCl3): 18.54; 20.53; 20.81; 21.52; 29.72; 53.10; 101.66; 118.52; 121.17; 124.35; 127.67; 129.65; 129.88;
131.63; 131.67; 132.58; 133.01; 134.25; 134.34; 135.31; 136.13; 137.70; 139.66; 140.52; 148.13; 149.56;
163.00; 191.77; 192.57. EI-MS: 480 (50, M+), 409 (28), 380 (13), 291 (27), 133 (100), 105 (47), 79 (20),
57 (29), 41 (16), 29 (7). Anal. calc. for C31H32N2O3 (480.61): C 77.47, H 6.71, N 5.83; found: C 77.6, H
6.7, N 5.7.
{2-[(1,1-Dimethylethyl)amino]-5-(pyridin-4-yl)furan-3,4-diyl}bis[(2,5-dimethylphenyl)methanone]
(4h). Yield: 82%. Yellow crystals. M.p. 90–928. IR (KBr): 3274 (NH), 1675, 1639 (C=O), 1595, 1550,
1
1459, 1410, 1339, 1280, 1048, 770. H-NMR (500 MHz, CDCl3): 1.65 (s, 9 H); 1.91 (s, 3 H); 2.08 (s, 3
H); 2.13 (s, 3 H); 2.25 (s, 3 H); 6.68 (d, J=1.3, 1 H); 6.73 (d, J=7.8, 1 H); 6.85 (dd, J=1.3, 7.7, 1 H);
6.93 (d, J=7.7, 1 H); 7.12 (dd, J=1.1, 7.8, 1 H); 7.25 (d, J=1.1, 1 H); 7.32 (d, J=6.4, 2 H); 8.48 (d,
J=6.4, 2 H); 8.78 (s, 1 H). 13C-NMR (125 MHz, CDCl3): 17.50; 19.60; 19.73; 20.54; 28.66; 52.21;
100.83; 117.09; 124.70; 126.64; 129.05; 129.16; 130.86; 131.17; 131.93; 132.52; 133.43; 133.55; 133.94;
135.22; 137.11; 137.84; 138.49; 148.95; 161.64; 190.49; 192.00. EI-MS: 480 (45, M+), 423 (7), 409 (57),
328 (8), 301 (10), 133 (100), 105 (40), 79 (15), 57 (23), 41 (12), 29 (7). Anal. calc. for C31H32N2O3
(480.61): C 77.47, H 6.71, N 5.83; found: C 77.3, H 6.8, N 5.7.
This research was supported by the Research Council of the University of Tehran (project No.
6102036/1/02).
REFERENCES
[1] B. H. Lipshutz, Chem. Rev. 1986, 86, 795.
[2] K. Nakanishi, ‘Natural Products Chemistry’, Kodansha, Tokyo, 1974.
[3] J. L. Duffy, T. A. Rano, N. J. Kevin, K. T. Chapman, W. A. Schleif, D. B. Olsen, M. Stahlhut, C. A.
Rutkowski, L. C. Kuo, L. Jin, J. H. Lin, E. A. Emini, J. R. Tata, Bioorg. Med. Chem. Lett. 2003, 13,
2569.

Helvetica Chimica Acta – Vol. 89 (2006)
303
[4] P. Ribereau, G. Queguiner, Can. J. Chem. 1983, 61, 334; P. Ribereau, G. Queguiner, Tetrahedron
1983, 39, 3593.
[5] C. Jutz, R. M. Wagner, A. Kroatz, H. G. Lobering, Justus Liebigs Ann. Chem. 1975, 5, 874.
[6] T. Umemoto, G. Tomizawa, Tetrahedron Lett. 1987, 28, 2705.
[7] L.-X. Zhao, Y.-S. Moon, A. Basnet, E.-K. Kim, Y. Jahng, J. G. Park, T. C. Jeong, W.-J. Cho, S.-U.
Choi, C. O. Lee, S.-Y. Lee, C.-S. Lee, E.-S. Lee, Bioorg. Med. Chem. Lett. 2004, 14, 1333.
[8] M. Adib, M. Mollahosseini, H. Yavari, M. H. Sayahi, H. R. Bijanzadeh, Synlett 2004, 1086.
[9] M. Adib, M. H. Sayahi, B. Aghaaliakbari, H. R. Bijanzadeh, Tetrahedron 2005, 61, 3963.
[10] M. Adib, K. Ghanbary, M. Mostofi, H. R. Bijanzadeh, Tetrahedron 2005, 61, 2645.
[11] I. Yavari, M. Adib, F. Jahani-Moghaddam, H. R. Bijanzadeh, Tetrahedron 2002, 58, 6901.
[12] I. Ugi, ‘Isonitrile Chemistry’, Academic Press, London, 1971.
[13] I. Ugi, Angew. Chem., Int. Ed. 1982, 21, 810.
[14] A. Dömling, I. Ugi, Angew. Chem., Int. Ed. 2000, 39, 3168.
[15] H. M. Walborsky, M. P. Periasamy, in ‘The Chemistry of Functional Groups: Supplement C’, Eds. S.
Patai, Z. Rappaport, Wiley, New York, 1983, Chapt. 20, p. 835–837.
[16] J. Szychowski, J. T. Wrobel, A. Leniewski, Can. J. Chem. 1977, 55, 3105.
[17] J. T. Wrobel, in ‘The Alkaloids’, Ed. R. H. F. Manske, Academic Press, New York, 1967, Vol. 9, p.
441; B. Maurer, G. Ohloff, Helv. Chim Acta 1976, 59, 1169.
[18] R. T. Lalonde, A. I. M. Tsai, C. J. Wang, C. F. Wong, Ger. Pat. 2603176, 1976 (Chem. Abstr. 1976, 85,
177750a).
[19] E. Wiegand, V. J. Bauer, S. R. Safir, J. Med. Chem. 1971, 14, 214.
[20] L. Skattebol, E. R. H. Jones, M. C. Whiting, Org. Synth., Coll. Vol. 4 1963, 792; K. Bowden, I. M.
Heilborn, E. R. H. Jones, B. C. Weedon, J. Chem. Soc. 1946, 39.
Received November 8, 2005