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tion was washed with aqueous saturated NaHCO3 (10 mL) and the
two resulting phases were separated; the organic phase (2-MeTHF)
was dried over anhydrous MgSO4, filtered, and dried in vacuo to
give 2 as a colorless solid (mp 1138C) in 96% yield (2.63 g), which
1
did not require further purification. H NMR (500 MHz, CDCl3, 258C,
TMS): d=7.79 (dd, J=5.5, 3.1 Hz, 2H, CH-Ar), 7.66 (dd, J=5.5,
3.1 Hz, 2H, CH-Ar), 4.36 (s, 2H, CH2), 3.68 ppm (s, 3H, CH3);
13C NMR (126 MHz, CDCl3, 258C): d=167.6 (CO), 167.3 (CO), 134.2
(CH), 131.9 (C), 123.5 (CH), 52.6 (CH2), 38.6 ppm (CH3); IR (KBr):
n˜ =1731, 1694, 1595, 1208, 909 cmÀ1; elemental analysis (%) for
C11H9NO4: calculated: C, 60.27; H, 4.14; N, 6.39, and measured:
C, 60.51; H, 4.01; N, 6.19.
Synthesis of amide 23
To a solution of 4-aminophenol (400 mg, 3.7 mmol, 1.0 eq.) in
2-MeTHF (9 mL), CaO (415 mg, 7.4 mmol, 2.0 eq., dried over night
over P2O5 in a desiccator) was added and the resulting suspension
was stirred at rt for 5 min. Afterwards, a solution of acetyl chloride
(306 mg, 3.9 mmol, 1.05 eq.) in 2-MeTHF (4 mL) was added drop-
wise over 5 min. The mixture was stirred for 4 h and subsequently
filtered in vacuo and washed with 2-MeTHF (12 mL). The solution
was washed with aqueous saturated NaHCO3 (8 mL) and the two
resulting phases were separated; the organic phase (2-MeTHF) was
dried over anhydrous MgSO4, filtered, and dried in vacuo to give
1
23 as a colorless solid (mp 1708C) in 93% yield (548 mg). H NMR
(300 MHz, [D6]DMSO, 258C, TMS): d=9.65 (s, 1H, NH), 9.13 (s, 1H,
OH), 7.34 (d, J=8.8 Hz, 2H, CH-Ar), 6.68 (d, J=8.8 Hz, 2H, CH-Ar),
1.98 ppm (s, 3H, CH3); 13C NMR (75 MHz, [D6]DMSO, 258C):
d=167.5 (CO), 153.1 (C), 131.0 (C), 120.8 (CH), 115.0 (CH), 23.7 ppm
(CH3); IR (KBr): n˜ =3430, 1662, 1591 cmÀ1; elemental analysis (%) for
C8H9NO2: calculated: C, 63.56; H,
Scheme 3. Acylation of alcohols and amines with enantiopure acyl chlorides
(paths 1–3) and the acylation of an enantiopure alcohol (path 4).
6.00; N, 9.27, and measured:
C, 63.70; H, 6.13; N, 9.12.
(See the Supporting Information
for full experimental procedures,
Scheme 4. Chemoselective protection of a secondary amine in the presence of a secondary alcohol during the
preparation of an N-aryloxazolidin-2-one.
compound characterization, and
1
copies of H and 13C NMR spectra).
No competitive ketene formation is observed for acylating
Acknowledgements
agents bearing acidic a-hydrogens. Furthermore, the proce-
dure allows the acylation of primary alcohols in a chemoselec-
Financial support from the University of Vienna and Austrian
Education Federal Ministry is gratefully acknowledged. Projects
CTQ2009-11801 from MICINN (Spanish Ministry of Science and In-
novation) and CTQ2012-32042 from MINECO (Spanish Ministry of
Economic Affairs and Competitiveness) are also acknowledged
for partial financial support.
tive manner in the presence of phenols or tertiary alcohols.
The proposed technique can also be used to acylate amines in
the presence of alcohol functionalities. The use of 2-MeTHF as
the solvent is crucial and it leads to maximized yields; it can
also prevent the need for chromatographic purifications.
Keywords: acylation · alcohols · amines · chemoselectivity ·
solvent effects
Experimental Section
Synthesis of ester 2
[1] J. Otera, J. Nishikido, Esterification: Methods, Reactions, and Applications,
Wiley-VCH, Weinheim, Germany, 2010.
[2] The Amide Linkage. Selected Structural Aspects in Chemistry, Biochemistry
and Materials Science (Eds.: A. Greenberg, C. M. Breneman, J. F. Lieb-
man), Wiley, New York, 2000.
[3] D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey, J. J. L. Leazer,
R. J. Linderman, K. Lorenz, J. Manley, B. A. Pearlman, A. Wells, A. Zaks,
To a solution of methanol (400 mg, 12.5 mmol, 1.0 eq.) in 2-MeTHF
(25 mL), CaO (1.40 g, 25.0 mmol, 2.0 eq., dried over night over P2O5
in a desiccator) was added and the resulting suspension was
stirred at rt for 5 min. Afterwards, a solution of phthaloyl chloride
(2.93 g, 13.1 mmol, 1.05 eq.) in 2-MeTHF (10 mL) was added drop-
wise over 5 min. The mixture was stirred for 6 h and subsequently
filtered in vacuo before washing with 2-MeTHF (20 mL). The solu-
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ChemSusChem 2013, 6, 905 – 910 909