Synthesis of N-acyl-β-aminoalcohols from N-acyloxazolidinones mediated by sodium azide

Article abstract of DOI:10.1016/S0040-4039(02)00155-7

N-Acyl-β-aminoalcohols were obtained efficiently via a highly endocyclic cleavage of N-acyloxazolidinones mediated by sodium azide in methanol at 40°C.

Full text of DOI:10.1016/S0040-4039(02)00155-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1961–1964
Synthesis of N-acyl-b-aminoalcohols from N-acyloxazolidinones
mediated by sodium azide
Abderrahim Bouzide* and Gilles Sauve´
INRS-Institut Armand Frappier, 531, Boulevard des Prairies, Laval, QC, Canada, H7V 1B7
Received 11 December 2001; revised 15 January 2002; accepted 17 January 2002
Abstract—N-Acyl-b-aminoalcohols were obtained efficiently via a highly endocyclic cleavage of N-acyloxazolidinones mediated
by sodium azide in methanol at 40°C. © 2002 Elsevier Science Ltd. All rights reserved.
N-Acyloxazolidinones have found widespread applica-
tion in the asymmetric syntheses.1 In addition to their
role as chiral auxiliaries, we studied N-acyloxazo-
lidinones as potential protecting groups of N-acyl-b-
aminoalcohols, which are found in several natural
products2 and in numerous drugs.3 In this paper, we
would like to report that the treatment of N-
acyloxazolidinones with sodium azide in methanol
afforded in high yields the corresponding N-acyl-b-
aminoalcohols.
obtained in only 33% yield while the carboxylic acid 3
resulting from an exocyclic cleavage4 was isolated as the
major product in 55% yield. Other bases such as NaOH
and KOH were attempted and gave identical results.
We found that the treatment of 2 with sodium azide in
methanol at 40°C yielded within 6 h the alcohol 4 as
the only reaction product in 95% yield (Scheme 2).
Recently, Silverman and co-workers reported the
hydrolysis of p-nitrobenzoic esters under the same con-
ditions.5 The intermediate carbonate 5 was isolated in
51% yield along with 22% of 4 when the reaction was
conducted at room temperature for 24 h. Replacement
of methanol with ethanol gave the carbonate 6 in 55%
yield accompanied with 17% of 4, whereas no reaction
took place when isopropanol was employed as the
solvent. The conversion of the carbonates 5 and 6 to 4
took place readily in the presence of water. The use of
sodium azide is essential for the accomplishment of the
oxazolidinone endocyclic cleavage and its replacement
with diphenylphosphoryl azide or trimethylsilyl azide
did not afford any trace of the desired b-hydroxyamide.
In connection with a program centered on HIV
protease inhibitors, we needed a series of compounds
containing N-acyl-b-aminoalcohol moiety as exem-
plified in 4 (Scheme 1). To prepare such a compound,
we proceeded first by a two-step synthesis: hydrolysis of
N-acyloxazolidinone 2 to the corresponding carboxylic
acid 3 followed by standard EDC coupling of 3 with
L
-phenylalaninol to obtain the desired product 4.
Although this two-step synthesis provided good yields,
we preferred a direct conversion of 2 to 4. First
attempts to hydrolyze 2 in an endocyclic manner with
LiOH in THF/H2O were unsuccessful and 4 was
Ph
OH
O
O
O
Ph
OH
O
O
O
H2N
b
a
N
O
N
O
OH
c
N
H
Ph
Ph
Ph
1
2
3
4
Ph
Ph
Scheme 1. Reagents and conditions: (a) NaHMDS, THF, BnBr, −40°C, 4 h, 91%, (b) LiOH, H2O2, H2O/THF, 5 h, 75%, (c) EDC,
iPr2NEt, CH2Cl2, 5 h, 72%.
* Corresponding author. Present address: Invenux Inc., 6840, N. Broadway, Suite F, Denver, CO 80221, USA.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00155-7

1962
A. Bouzide, G. Sau6e´ / Tetrahedron Letters 43 (2002) 1961–1964
Ph
OH
Ph
O
O
O
O
MeOH/H2O
97%
NaN3, ROH, RT
O
OR
N
O
N
H
N
H
2
O
4
Ph
Ph
Ph
5 R= Me, 51%
6 R= Et, 55%
Ph
NaN3, MeOH, 40oC, 95%
Scheme 2.
These results allowed us to gain insight into the reac-
tion mechanism. As proposed in Scheme 3, a nucle-
ophilic attack of sodium azide on the oxazolidinone
carbonyl occurs to produce the tetrahedral intermedi-
ate 7, which is followed by a ring opening to give 8.
Displacement of the azide group with methanol
affords the carbonate 5, which in the presence of
water underwent hydrolysis to give 4.
(15 mL) was added sodium azide (195 mg, 3 mmol).
The reaction was stirred at 40°C until complete con-
sumption of the starting material. To the suspension
was added water (1 mL) and the resulting limpid
solution was stirred for an additional 2 h. After cool-
ing, the reaction was diluted with water and EtOAc.
The aqueous layer was washed twice with EtOAc and
the combined organic layers were dried over MgSO4
and concentrated under reduced pressure. The crude
was purified by silica gel column chromatography
(EtOAc/hexanes=1:1) to afford 380 mg of the b-
hydroxyamide 4.6
As depicted in Table 1, other oxazolidinone deriva-
tives containing different auxiliary chirals and acyl
groups were subjected to the action of NaN3 in
MeOH or in EtOH. High to excellent yields of N-
acyl-b-aminoalcohols were isolated when the N-
acyloxazolidinones are a-branched as in 9–12.
Moderate yields, however, were obtained in the case
of unbranched N-acyloxazolidinones 13 and 1. It is
worth noting that the reaction is catalytic, as shown
when it was carried out with only 0.1 equiv. of
sodium azide (Table 1). The use of an excess of
NaN3 to reduce the reaction time was not inconve-
nient because it was easily separated from the reac-
tion by aqueous workup.
Typical procedure for the preparation of carbonate 5
from N-acyloxazolidinone 2: To a stirred solution of 2
(351 mg, 1 mmol) in methanol (15 mL) was added
sodium azide (195 mg, 3 mmol). The reaction was
stirred at room temperature for 24 h, then concen-
trated under reduced pressure and purified by silica
gel column chromatography (EtOAc/hexanes=1:4) to
afford 195 mg of the carbonate 5.6
In summary, N-acyl-b-aminoalcohols were obtained
efficiently and under almost neutral conditions by
endocyclic cleavage of N-acyloxazolidinone mediated
by sodium azide in methanol or in ethanol at 40°C.7
Typical procedure for the preparation of N-acyl-b-
aminoalcohols 4 from N-acyloxazolidinone 2: To a
stirred solution of 2 (351 mg, 1 mmol) in methanol
Ph
Na+
Ph
Ph
Ph
Na+
N3
O
O
OMe
O
O
N
MeOH
NaN3
O
N
O
O
N
O
O
NH
Ph
O
O
O
N3
Ph
Ph
Ph
2
8
7
5
Hydrolysis
Ph
O
NH OH
Ph
4
Scheme 3.

A. Bouzide, G. Sau6e´ / Tetrahedron Letters 43 (2002) 1961–1964
Table 1. NaN3-mediated endocyclic cleavage of N-acyloxazolidinone
1963
Conditions
N-Acyl-β-aminoalcohol
Yielda
N-Acyloxazolidinone
Ph
O
O
O
91%
66%
NaN3 (3 eq), MeOH
40oC, 15 h
OH
N
N
O
O
O
N
H
NaN3 (0.1 eq), MeOH
40oC, 4 days
9
14
Ph
Ph
O
O
O
OH
88%
92%
Ph
Ph
Ph
Ph
N
H
NaN3 (3 eq), MeOH
40oC, 8 h
10
15
Ph
O
O
Ph
O
OH
NaN3 (3 eq), MeOH
40oC, 15 h
N
N
H
Ph
11
16
Ph
O
O
O
OH
H
N
N
O
NaN3 (3 eq), MeOH
40oC, 20 h
83%
Ph
12
17
O
O
Ph
O
61%b
NaN3 (3 eq), EtOH
40oC, 4h
OH
OH
Ph
N
O
Ph
N
H
Ph
N
13
19
Ph
O
O
O
NaN3 (3 eq), EtOH
40oC, 8h
75%
N
H
O
1
18
Ph
a
Isolated yield after purification.
trans-Esterification byproduct, PhCH2CH2CO2Et, was isolated in 32% yield.
b
References
Murphy, J. A.; Emini, E. A.; Schleif, W. A.; Olsen, D. B.;
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Aldrichimica Acta 1997, 30, 3–12.
2. See for example: (a) Mapp, A. K.; Heathcock, C. H. J.
Org. Chem. 1999, 64, 23–27; (b) Zhang, X.; Rodrigues, J.;
Evans, L.; Hinkle, B.; Ballantyne, L. Pena, M. J. Org.
Chem, 1997, 62, 6420–6423; (c) Sarubbi, E.; Seneci, P. F.;
Angelastro, M. R.; Peet, N. P.; Denaro, M.; Islam, K.
FEBS Lett, 1993, 319, 253–256; (d) Stefanelli, S.; Cav-
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1995, 48, 332–334.
4. (a) Davies, S. G.; Doisneau, G. J.-M.; Prodger, J. C.;
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Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron
Lett. 1987, 28, 6141–6144.
5. Gomez-Vidal, J. A.; Forester, M. T.; Silverman, R. B.
Org. Lett. 2001, 3, 2477–2479; Gomez-Vidal, J. A.; Silver-
man, R. B. Org. Lett. 2001, 3, 2480–2484. These two
papers appeared while the present manuscript was in
preparation.
3. See for example, HIV-protease inhibitor, Indinavir: (a)
Dorsey, B. D.; McDonough, C.; McDaniel, S. L.; Levin,
R.; Newton, C. L.; Hoffman, J. M.; Dark, P. L.; Zugay-
6. Selected spectral data for compounds 4, 5, 14, 15 and 18.
1
Compound 4: White solid, H NMR (500 MHz, CDCl3) l

1964
A. Bouzide, G. Sau6e´ / Tetrahedron Letters 43 (2002) 1961–1964
0.96 (d, J=6.4 Hz, 3H), 1.05 (d, J=5.5 Hz, 3H), 1.96 (m,
NBA) m/z (%) 276 (MH+, 100), 258 (11), 154 (42). HRMS
calcd for C17H26NO2 276.196335, found 276.19680. Com-
pound 15: White solid, 1H NMR (500 MHz, CDCl3) l 2.17
(bs, 1H, OH), 2.20 (m, 1H), 2.30 (m, 1H), 2.41 (m, 1H), 2.65
and 2.85 (ABX, J=13.2 and 7.2 Hz, 2H), 2.78 (dd, J=13.2
and 6.1 Hz, 2H), 3.35 (ABX, J=13.0 and 7.1 Hz, 2H), 4.08
(m, 1H), 4.94 (d, J=10.0 Hz, 1H), 5.01 (d, J=15.0 Hz, 1H),
5.38 (d, J=6.3 Hz, 1H, NH), 5.50–5.62 (m, 1H), 7.10–7.32
(m, 10H). MS (CI, NBA) m/z (%) 324 (MH+, 100), 306 (42).
2H), 2.40 (bs, 1H, OH), 2.50 and 2.58 (ABX, J=13.5 and
7.0 Hz, 2H), 2.82–2.93 (m, 2H), 3.42 and 3.50 (ABX, J=11.2
and 5.6 Hz, 2H), 3.99 (m, 1H), 5.38 (d, J=6.3 Hz, 1H, NH),
6.96 (d, J=7.1 Hz, 2H), 7.17–7.29 (m, 8H). MS (CI, NBA)
m/z (%) 326 (MH+, 100). Compound 5: White solid, 1H
NMR (500 MHz, CDCl3) l 0.94 (d, J=7.1 Hz, 3H), 1.05
(d, J=6.6 Hz, 3H), 1.93 (m, 2H), 2.35 and 2.55 (ABX,
J=13.8 and 7.5 Hz, 2H), 2.88 (m, 2H), 3.77 (s, 3H, Me),
3.90 and 3.96 (ABX, J=11.2 and 5.6 Hz, 2H), 4.37 (m, 1H),
5.26 (d, J=8.6 Hz, 1H, NH), 6.90 (d, J=7.0 Hz, 2H),
7.18–7.29 (m, 8H). MS (CI, NBA) m/z (%) 384 (MH+, 84),
308 (100). Compound 14: White solid, 1H NMR (500 MHz,
CDCl3) l 0.87 (d, J=6.4 Hz, 3H), 0.92 (d, J=6.5 Hz, 3H),
1.73 (m, 2H), 2.20 (m, 2H), 2.80 and 2.90 (ABX, J=13.5
and 7.5 Hz, 2H), 3.40 (bs, 1H, OH), 3.62 (ABX, J=13.4 and
7.3 Hz, 2H), 4.20 (m, 1H), 4.83–5.00 (m, 2H), 5.50 (m, 1H),
6.00 (d, J=6.4 Hz, 1H, NH), 7.15–7.35 (m, 5H). MS (CI,
1
Compound 18: White solid, H NMR (500 MHz, CDCl3)
l 0.86 (d, J=6.3 Hz, 3H), 0.90 (d, J=6.5 Hz, 3H), 1.95–2.07
(m, 2H), 2.82 and 2.90 (ABX, J=13.5 and 7.5 Hz, 2H), 3.00
(bs, 1H, OH), 3.60 (dd, J=13.0 and 7.0 Hz, 1H), 3.70 (d,
J=11.2 Hz, 1H), 4.20 (m, 1H), 5.83 (d, J=1H, NH),
7.20–7.32 (m, 5H), MS (CI, NBA) m/z (%) 236 (MH+, 100),
218 (33).
7. All compounds were characterized by 1H NMR and MS and
are consistent with the assigned structures.