868
D. Kumar et al. / Tetrahedron Letters 49 (2008) 867–869
Table 1
References and notes
Synthesis of 5-(3-indolyl)oxazoles 6
1. (a) Bhate, D. S.; Hulyalker, R. K.; Menon, S. K. Experientia 1960, 16,
504; (b) Pettit, G. R.; Knight, J. C.; Herald, D. L.; Davenport, R.;
Pettit, R. K.; Tucker, B. E.; Schmidt, J. M. J. Nat. Prod. 2002, 65,
1793; (c) Joshi, B. S.; Taylor, W. I.; Bhate, D. S.; Karmarkar, S. S.
Tetrahedron 1963, 19, 1437; (d) Koyama, Y.; Yokose, K.; Dolby, L. J.
Agric. Biol. Chem. 1981, 45, 1285; (e) Noltenmeyer, M.; Sheldrick, G.
M.; Hoppe, H.-U.; Zeeck, A. J. Antibiot. 1982, 35, 549; (f) Umehara,
K.; Yoshida, K.; Okamoto, M.; Iwami, M.; Tanaka, H.; Kohsaka, M.;
Imanaka, H. J. Antibiot. 1984, 37, 1153; (g) Takahashi, S.; Matsunaga,
T.; Hasegawa, C.; Saito, H.; Fujita, D.; Kiuchi, F.; Tsuda, Y. Chem.
Pharm. Bull. 1998, 46, 1527; (h) Nishida, A.; Fuwa, M.; Fujikawa, Y.;
Nakahata, E.; Furuno, A.; Nakagawa, M. Tetrahedron Lett. 1998, 39,
5983; (i) N’Diaye, I.; Guella, G.; Mancini, I.; Pietra, F. Tetrahedron
Lett. 1996, 37, 3049.
2. Koser, G. F. Adv. Heterocycl. Chem. 2004, 86, 225.
3. Koser, G. F.; Relenyi, A. G.; Kalos, A. N.; Rebrovic, L.; Wettach, R.
H. J. Org. Chem. 1982, 47, 2487.
4. (a) Kelly, T. R.; Fu, Y.; Xie, R. L. Tetrahedron Lett. 1999, 40, 1857; (b)
Doyle, K. J.; Moody, C. J. Synthesis 1994, 1021; (c) Roy, S.; Haque, S.;
Gribble, G. W. Synthesis 2006, 3948; (d) Brain, C. T.; Paul, J. M.
Synlett 1999, 1642; (e) Nishada, A.; Fuwa, M.; Naruto, S.; Sugano, Y.;
Saito, H.; Nakagawa, M. Tetrahedron Lett. 2000, 41, 4791.
5. Liu, S. F.; Wu, Q.; Schmider, H. L.; Aziz, H.; Hu, N.-X.; Popovic, Z.;
Wang, S. J. Am. Chem. Soc. 2000, 122, 3671.
Entry
R
Yielda (%)
Overall
Mp (°C)
yieldb (%)
4
5
6
1
2
3
4
5
a
Phenyl
Methyl
Ethyl
i-Butyl
Benzyl
68
79
79
74
75
82
80
76
74
72
83
82
73
73
76
29
32
27
24
25
216
1964
1564
1441
172
Yield of isolated pure products.
Five steps.
b
potent 5-(3-indolyl)oxazoles. Many procedures have been
developed for the construction of 5-(3-indolyl)oxazoles.4
However, some of these procedures often utilize toxic
and costly reagents, and afford products in only moderate
yields. Thus, it is desirable to develop a straightforward
and environmentally benign method to synthesize 5-(3-
indolyl)oxazoles (Scheme 1).
Our synthesis of 5-(3-indolyl)oxazoles (6) started from 3-
acetyl-1-benzenesulfonylindole (1).5,6 The synthesis of novel
3-tosyloxyacetyl-1-benzenesulfonylindole (2) was accom-
plished by reaction of 1 with hydroxy(tosyloxy)iodobenzene
in an excellent yield (86%) at room temperature.7 The reac-
tion of unprotected 3-acylindole with hydroxy(tosyl-
oxy)iodobenzene led to a complex mixture without any
trace of the desired 3-tosyloxyacetylindole. 3-Amino-
acetyl-1-benzenesulfonyl indole hydrochloride (3) was
obtained in very good yield from the reaction of 2 with
hexamethylenetetraamine (HMTA) followed by refluxing
the reaction mixture in the presence of dilute hydrochloric
acid. Compound 3 was acylated with the appropriate acyl
chloride in the presence of triethylamine to give acyl-
aminoketones 4.
Cyclodehydration of acylaminoketones 4 to give 5-(3-
indolyl)oxazoles (5) was accomplished successfully using
p-toluenesulfonic acid. Generally, cyclodehydration of
acylaminoketones into oxazoles involves harsh reagents
such as H2SO4, PCl5, P2O5, SOCl2, POCl3, Ac2O and
Ph3P. Finally, the benzenesulfonyl moiety of 5-(3-indolyl)-
oxazoles 5 was removed using dilute sodium hydroxide
to afford the 5-(3-indolyl)oxazoles 6 in good yields.
Similarly, other analogues of 5-(3-indolyl)oxazoles 6
were prepared and their melting points and spectral
data were in excellent agreement with those reported
(Table 1).1,4
In summary, we have developed a facile and high yield-
ing protocol for the synthesis of 5-(3-indolyl)oxazoles 6
from readily available starting materials. This general pro-
tocol can be used to prepare a series of 5-(3-indolyl)oxazole
analogues.
6. Ketcha, D. M.; Gribble, G. W. J. Org. Chem. 1985, 50, 5451.
7. 3-Tosyloxyacetyl-1-benzenesulfonylindole (2): A mixture of 3-acetyl-1-
benzenesulfonylindole
1 (3.0 g, 10.0 mmol) and [hydroxy(tosyl-
oxy)iodo]benzene (4.72 g, 12.0 mmol) was stirred in acetonitrile at
room temperature for 8 h. After completion of the reaction, as
monitored by TLC, the solvent was distilled off and the residue
obtained was crystallized from methanol to afford pure 3-tosyloxy-
acetyl-1-benzenesulfonylindole 2: (4.03 g, 86%); mp 138–140 °C; IR
1
(KBr) cmÀ1 = 3147, 2983, 1693, 1597, 1174, 1143, 1087, 873 cmÀ1; H
NMR (400 MHz, CDCl3): d = 2.40 (s, 3H, CH3), 5.02 (s, 2H, CH2),
7.30–7.40 (m, 4H, Ar-H), 7.51–7.55 (m, 2 H, Ar-H), 7.61–7.63 (m, 1H,
Ar-H), 7.83 (d, 2H, J = 8.40 Hz, Ar-H), 7.94–8.00 (m, 3H, Ar-H), 8.21
(dd, 1H, J = 1.2, 8.0 Hz, Ar-H), 8.36 (s, 1H, Ar-H); 13C NMR
(100 MHz, CDCl3): d = 21.74, 70.70, 113.15, 117.75, 122.98, 125.25,
126.28, 127.33, 127.49, 128.23, 129.85, 130.13, 132.44, 132.82, 134.51,
134.88, 137.40, 145.63, 186.93; MS (EI), m/z [M+H]+ = 470.0; Anal.
Calcd for C23H19NO6S2: C, 58.83; H, 4.08; N, 2.98. Found: C, 59.07;
H, 3.74; N, 3.43.
3-Aminoacetyl-1-benzenesulfonylindole hydrochloride (3): To a stirred
solution of hexamethylenetetramine (1.41 g, 10 mmol) in 10 mL of
chloroform was added 3-tosyloxyacetyl-1-benzenesulfonylindole
2
(4.0 g, 8.5 mmol) over a period of 1 h. The solution was stirred under
reflux for 3 h and allowed to stand overnight. Upon cooling, the
precipitated salt was filtered and dried. The ammonium chloride
formed in the reaction was removed by dissolving the crude salt in a
warm solution of water, ethanol and 12N hydrochloric acid (1:4:1, v/v).
Pure 3 precipitated from the above homogeneous solution which was
filtered and recrystallized from methanol-dichloromethane (1:2) and
dried. (2.71 g, 91%); mp 220 °C (dec.); IR (KBr) cmÀ1 = 3248, 3088,
1681, 1606, 1514, 1211, 1000, 750; 1H NMR (400 MHz, DMSO-d6)
d = 4.80 (s, 2H, CH2), 7.08 (d, 2H, J = 7.84 Hz, Ar-H), 7.51–7.55 (m,
2H, Ar-H), 7.36–7.43 (m, 2H, Ar-H), 7.66 (d, 2H, J = 8.00 Hz, Ar-H),
7.96 (d, 1H, J = 5.96 Hz, Ar-H), 8.14 (d, 2H, J = 7.80 Hz, Ar-H), 8.20
(d, 1H, J = 7.72 Hz, Ar-H), 8.98 (s, 1H); 13C NMR (100 MHz, DMSO-
d6) d = 58.06, 112.76, 118.00, 121.96, 125.32, 127.15, 127.98, 129.52,
133.86, 134.63, 135.04, 136.21, 138.28, 144.02, 186.19; MS (EI), m/z
[M]+ = 314.0; Anal. Calcd for C16H15ClN2O3S: C, 54.78; H, 4.31; N,
7.99. Found: C, 54.47; H, 4.22; N, 7.57.
Acknowledgement
3-(Benzoylamidoacetyl)-1-benzenesulfonylindole (4): 3-aminoacetyl-1-
benzenesulfonylindole hydrochloride 3 (0.3 g, 0.86 mmol) was dis-
solved in dichloromethane (5 mL) followed by dropwise addition of
We thank the University Grants Commission, New
Delhi for financial support (Project F. No. 32-216/2006).