S. Madabhushi et al. / Tetrahedron Letters 52 (2011) 6103–6107
6107
solution, dried over anhy. Na2SO4, and concentrated under reduced pressure.
The crude product was purified by normal column chromatography (silica gel
60–120 mesh, ethyl acetate/hexane: 1:4) to obtain acetanilide 2a (0.89 g, 80%,
mp 114–116 °C) and acetophenone oxime 3a (76 mg, 7%, mp 55–60 °C) in the
form of white powders.
work is the first method for the direct conversion of a (2-hydroxy-
aryl) ketone directly into benzoxazole.12
In our study, (2-hydroxyaryl) ketones were converted into
benzoxazoles only under microwave heating. They gave mixtures
of the corresponding amide and oxime under reflux in acetonitrile
and the results obtained with (2-hydroxy) acetophenone under
these conditions are shown as a typical example in Scheme 4.
In summary, this work shows an unprecedented efficient
one-step method for the synthesis of amides from ketones and
benzoxazoles from the reaction of (2-hydroxyaryl) ketones with
acetohydroxamic acid using sulfuric acid as a catalyst in acetoni-
trile. In this study, amides were formed in good yields both under
conventional and microwave heating conditions and we obtained
benzoxazoles only with microwave heating. In both methods, the
reaction times were found to be very short (<15 min) under micro-
wave heating conditions.
Spectral data obtained for 2a: 1H NMR (300 MHz, CDCl3): d = 7.64 (bs, 1H,
exchangeable with D2O), 7.44–7.51 (d, J = 7.9 Hz, 2H), 7.23–7.31 (t, J = 7.9 Hz,
2H), 7.02–7.09 (t, J = 7.9 Hz, 1H), 2.14 (s, 3H); 13C NMR (75 MHz, CDCl3):
d = 169.2, 138.3, 129.2, 124.6, 120.4, 24.8; IR (neat):
t 3245, 3070, 2960, 2833,
1654, 1607, 1511, 1369, 1243, 1027, 830, 770, 526 cmÀ1; EIMS (m/z, %): 135
(M)+, 93, 77. Exact mass observed for C8H9NO: 135.1635 (calcd: 135.1613).
Spectral data obtained for 3a: 1H NMR (300 MHz, CDCl3): d = 9.42 (bs, 1H,
exchangeable with D2O), 7.54–7.62 (m, 2H), 7.32–7.41 (m, 3H), 2.31 (s, 3H); 13
C
NMR (75 MHz, CDCl3): d = 158.7, 157.6, 130.5, 127.6, 118.4, 117.4, 14.5; IR
(neat):
t
3380, 2924, 1620, 1574, 1494, 1292, 1257, 989, 643 cmÀ1; EIMS (m/z,
%): 135 (M)+, 118, 103, 77, 51. Exact mass observed for C8H9NO: 135.0684
(calcd: 135.0632).
Typical procedure for the preparation of amide under microwave heating:
Acetophenone 1a (1.0 g, 8.3 mmol), acetohydroxamic acid (0.92 g,
12.5 mmol), acetonitrile (3 ml), and conc. H2SO4 (0.2 ml) were taken into a
10 ml pressure tube and subjected to microwave heating (CEM discover,
360 W, 80 °C, 25 psi) for 10 min. The crude product obtained was purified as
mentioned above to afford acetanilide 2a (0.94 g, 86%) and it gave spectral data
same as above.
Acknowledgments
10. For some recent examples, see: (a) Oksuzoglu, E.; Tekiner-Gulbas, B.; Alper, S.;
Temiz-Arpaci, O.; Ertan, T.; Yildiz, I.; Diril, N.; Sener-Aki, E.; Yalcin, I. J. Enzyme
Inhib. Med. Chem. 2008, 23, 37–42; (b) McKee, M. L.; Kerwin, S. M. Bioorg. Med.
Chem. 2008, 16, 1775; (c) Johnson, S. M.; Connelly, S.; Wilson, I. A.; Kelly, J. W. J.
Med. Chem. 2008, 51, 260–270; (d) Harikrishnan, L. S.; Kamau, M. G.; Herpin, T.
F.; Morton, G. C.; Liu, Y.; Cooper, C.; Salvati, M. E.; Qiao, J. X.; Wang, T. C.; Adam,
L. P.; Taylor, D. S.; Chen, A. Y. A.; Yin, X.; Seethala, R.; Peterson, T. L.; Nirschl, D.
S.; Miller, A. V.; Weigelt, C. A.; Appiah, K. K.; O’Connell, J. C.; Lawrence, R. M.
Bioorg. Med. Chem. Lett. 2008, 18, 2640–2644; (e) Ueda, S.; Nagasawa, H. J. Org.
Chem. 2009, 74, 4272–4277; (f) Lokwani, P.; Nagori, B. P.; Batra, N.; Goyal, A.;
Gupta, S.; Singh, N. J. Chem. Pharm. Res. 2011, 3, 302–311.
C.N. is thankful to the UGC, New Delhi; J.R., G.K.R., and M.K.K.R
are thankful to the CSIR, New Delhi for the award of Junior
Research Fellowships. B.C.R. is thankful to the CSIR, New Delhi
for the award of Senior Research Fellowship.V. V.S. is thankful to
the Director, IICT for financial support in the form of fellowship.
References and notes
11. (a) Sardarian, A. R.; Shahsavari-Fard, Z. Synlett 2008, 1391–1393; (b) Loupy, A.;
Regnier, S. Tetrahedron Lett. 1999, 40, 6221–6224; (c) Haley, M. F.; Yates, K. Can.
J. Org.Chem. 1987, 52, 1825–1830; (d) Stokker, G. J. Org. Chem. 1983, 48, 2613–
2615.
1. (a) Patai, S. Chemistry of Carbon–Nitrogen Double Bond; Wiley: London, 1970. pp
409–439; (b) Atta-ur-Rahman Studies in Natural products; Elsevier Science,
2000. p 24; (c) Wasserman, H. H. Nature 2006, 441, 699–700.
2. (a) Arisawa, M.; Yamaguchi, M. Org. Lett. 2001, 3, 311–312; (b) De Luca, L.;
Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2002, 67, 6272–6274; (c) Boruah, M.;
Konwar, D. J. Org. Chem. 2002, 67, 7138–7139; (d) Iranpoor, N.; Firouzabadi, H.;
Aghapour, G. Synth. Commun. 2002, 32, 2535–2541; (e) Chandrasekhar, S.;
Gopalaiah, K. Tetrahedron Lett. 2003, 44, 755–756.
3. Ritz, J.; Fuchs, H.; Kieczka, H.; Moran, W. C. In Caprolactam. Ullmann’s
Encyclopedia of Industrial Chemistry; Cambell, F. Th., Pfefferkorn, R.,
Rounsaville, J. R., Eds.; Wiley-VCH: Weinheim, 1986; Vol. 5, pp 31–50.
4. Sharghi, H.; Hosseini, M. Synthesis 2002, 1057–1060.
5. Griffith, D. P.; Gleeson, M. J.; Lee, H.; Longuet, R.; Deman, E.; Earle, N. Eur. Urol.
1991, 20, 243–247.
6. Tkac, P.; Matteson, B.; Bruso, J.; Paulenova, A. J. Radioanal. Nucl. Chem. 2008,
277, 31–36.
7. Sridhar, M.; Narsaiah, C.; Raveendra, J.; Reddy, G. K.; Reddy, M. K. K.;
Ramanaiah, B. C. Tetrahedron Lett. 2011, 52, 4701–4704.
8. (a) Beckmann, E. Ber. Dtsch. Chem. Ges. 1886, 19, 988–993; (b) Donaruma, L. G.;
Heldt, W. Z. Org. React. 1960, 11, 1–156; (c) Gawley, R. E. Org. React. 1988, 35, 1–
420.
9. Typical procedure for the preparation of amide under conventional heating:
Acetophenone 1a (1.0 g, 8.3 mmol), acetohydroxamic acid (0.92 g, 12.5 mmol),
acetonitrile (10 ml), and conc. H2SO4 (0.2 ml) were taken into a 25 ml round
bottomed flask fitted with a condenser and calcium chloride guard tube. The
mixture was refluxed and the progress of the reaction was monitored by tlc.
After completion of the reaction (8.5 h), the reaction mixture was cooled to
room temperature and diluted with ethyl acetate (5 ml). Next, saturated
sodium bicarbonate solution (10 ml) was added drop-wise to the mixture for
the neutralization of sulfuric acid and then extracted with ethyl acetate
(2 Â 10 ml). The combined organic layer was washed with saturated NaCl
12. Typical procedure for the preparation of benzoxazoles under microwave heating: 2-
Hydroxy acetophenone 4a (1.0 g, 7.4 mmol), acetohydroxamic acid (0.83 g,
11.0 mmol), acetonitrile (3 ml), and conc. H2SO4 (0.2 ml) were taken into a
10 ml pressure tube and subjected to microwave heating (CEM discover,
360 W, 80 °C, 25 psi) for 8 min. Next, the reaction mixture was diluted with
ethyl acetate (3 ml) and to this; saturated sodium bicarbonate solution (5 ml)
was added drop-wise. The mixture was extracted with ethyl acetate
(2 Â 10 ml) and the combined organic layer was washed with saturated NaCl
solution, dried over anhy. Na2SO4, and concentrated under reduced pressure.
Purification of the mixture by normal column chromatography (silica gel 60–
120 mesh, ethyl acetate/hexane: 1:9) gave benzoxazole 5a (0.67 g, 70%) in the
form of a yellow oil and 2-hydroxy acetophenone oxime 6a (68 mg, 6%, mp
104–107 °C) in the form of a white powder.
Spectral data obtained for 5a: 1H NMR (300 MHz, CDCl3): d = 7.60–7.63 (m, 1H)
7.39–7.42 (m, 1H), 7.22–7.26 (m, 2H), 2.63 (s, 3H); 13C NMR (75 MHz, CDCl3):
d = 163.6, 150.9, 141.3, 124.4, 124.1, 119.4, 110.1, 14.4; IR (neat):
t 2927, 2846,
1701, 1639, 1546, 1525, 1493, 1444, 1243, 1024, 816, 720 cmÀ1; EIMS (m/z, %):
133 (M)+,118, 92, 52. Exact mass observed for C8H7NO: 133.0528 (calcd:
135.0473).
Spectral data obtained for 6a: 1H NMR (300 MHz, CDCl3): d = 11.52 (bs, 1H,
exchangeable with D2O), 8.13 (bs, 1H, exchangeable with D2O), 7.37–7.40 (d,
J = 8.3 Hz, 1H), 7.19–7.25 (t, J = 8.3,6.7 Hz,1H), 6.91–6.95 (d, J = 6.7 Hz, 1H),
6.83–6.88 (t, J = 8.3, 6.7 Hz,1H), 2.35 (s, 3H); 13C NMR (75 MHz, CDCl3):
d = 159.4, 157.3, 130.8, 127.6, 119.4, 117.2, 10.8; IR (neat):
t 3380, 2924, 1620,
1574, 1494, 1292, 1257, 989, 643 cmÀ1; EIMS (m/z, %): 151 (M+), 134, 119, 93,
41. Exact mass observed for C8H9NO2: 151.1525 (calcd: 151.1519).