P.-Q. Huang et al. / Tetrahedron Letters 42 (2001) 9039–9041
9041
after 2 h at rt (entries 7–9), while in the reaction of
n-butyl acetate with i-Bu2AlH–HNEt2, the yield was
only 72% (entry 10). However, the aminolysis of n–
butyl acetate with i-Bu2AlH–HNEt2·HCl proceeded in
high yield (entry 11). In such a way, the Weinreb amide
12 was prepared in a yield of 91% (entry 12).
3. White, J. M.; Tunoori, A. R.; Georg, G. I. J. Am. Chem.
Soc. 2000, 122, 11195–11196.
4. For recent examples, see: (a) Tunoori, A. R.; White, J. M.;
Georg, G. I. Org. Lett. 2001, 2, 4091–4093; (b) Lee, J. I.;
Park, H. Bull. Korean Chem. Soc. 2001, 22, 421–423.
5. (a) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron
Lett. 1977, 4171–4174; (b) Levin, J. I.; Turos, E.; Weinreb,
S. M. Synth. Commun. 1982, 12, 989–993; (c) Lipton, M.
F.; Basha, A.; Weinreb, S. M. Org. Synth. 1979, 59, 49; (d)
Sidler, D. R.; Lovelace, T. C.; McNamara, J. M.; Reider,
P. J. J. Org. Chem. 1994, 59, 1231–1233.
6. (a) Liu, W. M.; Xu, D. D.; Repic, O.; Blacklock, T. J.
Tetrahedron Lett. 2001, 42, 2439–2441; (b) Williams, J. M.;
Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling, U.
H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461–
5464; (c) Iseki, K.; Asada, D.; Kuroki, Y. J. Fluorine
Chem. 1999, 97, 85–89.
7. See for example: (a) Rebek, Jr., J.; Beerli, R. Tetrahedron
Lett. 1995, 36, 1813–1816; (b) Shibasaki, M.; Nakamura,
S. Tetrahedron Lett. 1994, 35, 4145–4148; (c) Evans, D. A.;
Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am.
Chem. Soc. 1990, 112, 7001–7031; (d) Garigipati, R. S.;
Tschaen, D. M.; Weinreb, S. M. J. Am. Chem. Soc. 1985,
107, 7790–7792.
Next, we examined the aminolysis of less reactive aro-
matic esters. Treatment of ethyl benzoate 3 with 5 mol
equiv. of i-Bu2AlH–NH2C5H11-i or i-Bu2AlH–NH2Bn
yielded amide 13 or 14 in 94 and 95% yields, respec-
tively. For the aminolysis of ethyl benzoate with i-
Bu2AlH–HNEt2·HCl, a prolonged reaction time (20 h
at 45°C) was necessary to ensure a reasonable yield of
amide 15.
Finally, the method was extended to cyclic amines
(entries 16–18). In this way, fasoracetam 18, a novel
cognition enhancer, was prepared from (S)-methyl
pyroglutamate in a yield of 52%.
In summary, we have developed convenient and mild
methods for amide synthesis by aminolysis of lactones
or esters with DIBAL–H–H2NR or DIBAL–H–
HNR1R2·HCl.9 Conditions have been defined for the
preparation of both secondary and tertiary amides,
including Weinreb amides in excellent yields. The major
advantage of the present method resides on the success-
ful substitution of Me3Al or Me2AlCl by i-Bu2AlH
(DIBAL–H). Compared with other organoaluminium
reagents such as Me3Al or Me2AlCl, DIBAL–H, a
routinely used reducing reagent, is much more popular.
Hence, the present method constitutes an important
modification to the well known Weinreb methodology.
The nature of the reactive species in the present aminoly-
sis reaction is being investigated in these laboratories.
8. (a) Shimizu, T.; Osako, K.; Nakata, T. Tetrahedron Lett.
1997, 38, 2685–2688; (b) Murakami, N.; Nakajima, T.;
Kobayashi, M. Tetrahedron Lett. 2001, 42, 1941–1943.
9. General procedure: A solution of DIBAL–H (1.5 M in
toluene, 2.58 mL, 3.87 mmol) was added to a cooled
(0–5°C) solution of i-pentylamine (0.47 mL, 4.0 mmol) in
THF (1.7 mL) under nitrogen. The mixture was allowed to
warm up and stirred at rt for 2 h. The concentration of the
prepared DIBAL–H–i-C5H11NH2 complex was about 0.88
M, and was used directly for aminolysis. To a solution of
ethyl benzoate (0.095 mL, 0.67 mmol) in THF (2.5 mL)
was added, under nitrogen at rt, the DIBAL–H–i-
C5H11NH2 complexes (3.8 mL, ꢀ3.35 mmol). After stir-
ring at rt for 2 h, the reaction was cooled to 0°C, and then
quenched with H2O (1.5 mL) and a 1 M aqueous solution
of KHSO4 (4 mL). The resulting mixture were extracted
with CH2Cl2 (3×10 mL). The combined organic layers
were washed with brine, dried over Na2SO4 and concen-
trated. The residue was purified by flash chromatography
(EtOAc/PE: 1/4) to give amide 13 (120 mg, yield 94%) as
white crystals. Mp 52ꢀ53°C. IR: 3317, 3065, 3027, 2957,
2930, 2870, 1639, 1603, 1579, 1543, 1491, 1468, 1368, 1310,
Acknowledgements
The authors are grateful to the National Science Fund
for Distinguished Young Investigators (29625204), the
NSF of China (29832020, 20072031), Qiu Shi Science &
Technologies Foundation, Foundation for University
Key Teacher by the Ministry of Education and Xiamen
University for financial support.
1224, 1153, 1076, 1025, 805, 695 cm−1 1H NMR (500
.
References
MHz, CDCl3): 0.98 (d, J=6.6 Hz, 6H, 2CH3), 1.48–1.56
(m, 2H, H-3%), 1.64–1.75 (m, 1H, H-4%), 3.44–3.52 (m, 2H,
H-2%), 7.40–7.79 (m, 5H, Ph-H). HRESIMS calcd for
[C12H17NO+H]+ 192.1383, found 192.1385. Anal. calcd for
C12H17NO: C, 75.39; H, 8.90; N, 7.33; found: C, 75.38; H,
9.00; N, 7.28.
1. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22,
3815–3818.
2. For a review on the application of N-methoxy-N-methyl-
amides, see: Sibi, M. P. Org. Prep. Proced. Int. 1993, 25,
15–40.