of interest to the synthetic community. The conversion of
N-acyloxazolidinones to esters using rare earth Lewis acid
has been recently reported by Otera and co-workers.
Table 1. Conversion of N-Benzoyloxazolidinone to
O-Benzylhydroxamidea
6
Similarly, the conversion of acyl oxazolidinones to N,O-
7
dimethylhydroxamides (Weinreb amides) using trimethyl-
8
aluminum has also been noted in the literature. The
chemoselectivity, exo or endo attack, in these reactions are
well controlled, and only the product arising from exo attack
9
is observed. In a program aimed at developing methods for
entry Lewis acid (equiv) amine (equiv) solventb yield, %
c
the preparation of succinate based MMP inhibitors, we
became interested in the efficient conversion of oxazolidi-
nones to hydroxamic acids. This paper details one such
process.
1
2
3
4
5
6
7
8
9
0
1
Sm(OTf)3 (1.0)
Sm(OTf)3 (1.0)
Sm(OTf)3 (1.0)
Sm(OTf)3 (1.0)
Sm(OTf)3 (0.5)
Sm(OTf)3 (0.3)
Yb(OTf)3 (1.0)
Yb(OTf)3 (1.0)
Eu(OTf)3 (1.0)
Eu(OTf)3 (1.0)
La(OTf)3 (1.0)
La(OTf)3 (1.0)
2
2
2
5
2
2
2
2
2
2
2
2
THF
ether
CH3CN
THF
THF
THF
THF
ether
THF
ether
THF
ether
90
83
88
91
90
78
68
50
80
85
50
80
Our initial goal was to evaluate lanthanide triflates as
catalysts for the conversion of acyloxazolidinones to hy-
droxamic acids. The catalyst choice was based on several
unique properties of the rare earth Lewis acids: (1) ready
availability, (2) a large number of triflates with varied Lewis
acidity, (3) compatibility with amine nucleophiles, and (4)
potential for reactions in aqueous medium. Our experiments
began with the optimization of reaction conditions for the
conversion of N-benzoyl-4-benzyl-2-oxazolidinone 3 to O-
benzylbenzohydroxamic acid 4 (eq 2), and these results are
shown in Table 1. Treatment of 3 with 2 equiv of O-
benzylhydroxylamine in THF at room temperature gave the
hydroxamic acid 4 in 90% isolated yield (entry 1). Ether or
acetonitrile were equally efficient as a solvent in the
amidation reaction (entries 2 and 3). Increasing the number
of equivalents of the amine nucleophile to 5 led to moderate
improvements in reaction time (2 h for entry 2 and 0.5 h for
entry 4). However, the yield did not improve. Substoichio-
metric amounts of the catalyst (30 mol %) also gave 4 in
high yields (Table 1, entry 6). Of the other rare earth Lewis
acids evaluated (entries 7-12), europium and lanthanum
triflates also showed good reactivity (entries 9, 10, and 12).
Having established that the amidation sequence was
feasible, we turned our attention to examining the scope of
the nucleophiles in these reactions, and these results are
shown in Table 2 (eq 3). Treatment of the achiral oxazoli-
1
1
12
a
Reactions were carried out at rt. b An average concentration of 0.1-
0.2 M was employed. c Isolated yields for column purified materials.
dinone 6 with a variety of hydroxylamines gave 7 in
moderate to good yields depending on the amine. As
described previously, reaction with O-benzylhydroxylamine
proceeds in high yield (entry 1). The reaction proceeds
equally well with the amine hydrochloride salt with in situ
neutralization (entry 2). Reaction with the parent hydroxy-
lamine was less efficient (entry 3). Reactions with silylated
hydroxylamines gave the hydroxamic acid directly in moder-
ate yields (entries 4 and 5). The THP-protected hydroxy-
lamine served as a better synthon for the parent hydroxy-
Table 2. Evaluation of Different Hydroxylaminesa,b
(
4) The direct conversion of acyl thiazolidine thiones to hydroxamic acid
derivatives has been reported. (a) Jung, M.; Miller, M. J. Tetrahedron Lett.
985, 26, 977. (b) Hsiao, C.-N.; Ashburn, S. P.; Miller, M. J. Tetrahedron
Lett. 1985, 26, 4855. (c) Miller, M. J. Acc. Chem. Res. 1986, 19, 49.
5) (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichim. Acta 1997, 30,
. (b) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96, 835. (c)
Evans, D. A. Aldrichim. Acta 1982, 15, 23. (d) Sibi, M. P. Aldrichim. Acta
999, 32, 93.
1
(
3
product
1
c
entry
amine (equiv)
R
R1
yield, %
(
(
6) Orita, A.; Nagano, Y.; Hirano, J.; Otera, J. Synlett 2001, 637.
7) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815. (b)
1
2
3
4
5
6
7
8
BnONH2 (2)
BnONH2 (2)
HONH2
TMSONH2
TMSONHTMS
THPONH2
H
H
H
H
H
H
H
Me
Bn
Bn
H
H
H
98
For reviews on Weinreb amides, see: Sibi, M. P. Org. Prep. Proced. Intl.
98d
45d
39
1
993, 25, 15. (b) Mentzel, M.; Hoffmann, H. M. R. J. Prakt. Chem. 1997,
3
39, 517.
(
8) Conversion of N-acyl oxazolidinones to Weinreb amides. Evans, D.
A.; Miller, S. J.; Ennis, M. D.; Ornstein, P. L. J. Org. Chem. 1992, 57,
067. Convesrion of esters to Weinreb amides. Williams, J. M.; Jobson, R.
55
70
75
1
H
B.; Yasuda, N.; Marchesini, G.; Dolling, U.-H.; Grabowski, E. J. J.
Tetrahedron Lett. 1995, 36, 5461. Garigipati, R. S.; Tschaen, D. M.;
Weinreb, S. M. J. Am. Chem. Soc. 1985, 107, 7790.
4-OMePhCH2ONH2
MeONHMe
4-MeOBn
Me
75d
(
9) N-Acyl oxazolidinones can be selectively cleaved either at the exo
a
Reactions were carried out at room temperature. b An average concen-
or at the endo site. Exo cleavage: Evans, D. A.; Ellman, J. A.; Dorow, R.
L. Tetrahedron Lett. 1987, 28, 1123. Evans, D. A.; Sjogren, E. B.; Bartroli,
J. Dow, R. L. Tetrahedron Lett. 1986, 27, 4957. Jacobi, P. A.; Zhang, W.
Tetrahedron Lett. 1993, 34, 2585. Endo cleavage: Ishizuka, T.; Kunieda,
T. Tetrahedron Lett. 1987, 28, 4185. Evans, D. A.; Weber, A. E. J. Am.
Chem. Soc. 1987, 109, 7151.
c
tration of 0.1-0.2 M was employed. Isolated yields for column purified
materials. d The reaction was carried out by in situ generation of the amine
(4 equiv) from the corresponding hydrochloride using triethylamine (3.8
equiv).
3344
Org. Lett., Vol. 4, No. 20, 2002